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1. Disentangling the genetics of lean mass

Author

Tuomas O. Kilpeläinen, Jacqueline S. L. Kloth, Nam H. Cho, Peter Vollenweider, Georg Homuth, Unnur Thorsteinsdottir, Nicole C. Wright, Wen-Chi Chou, Yongmei Liu, Kari Stefansson, Kim M. Huffman, Ida Malkin, Andrew P. Morris, Robert Luben, Shad B. Smith, Lei Yu, Joel Eriksson, Aarno Palotie, Veikko Salomaa, Michael J. Econs, Liesbeth Vandenput, Elizabeth A. Streeten, Albert Hofman, Elisabeth Widen, Emmi Tikkanen, Braxton D. Mitchell, Natasja M. van Schoor, Caroline Hayward, Liisa Byberg, Joanne M. Jordan, Bruce M. Psaty, Elisabeth Steinhagen-Thiessen, Magnus Karlsson, Harry Campbell, John C. Chambers, Fernando Rivadeneira, Johan G. Eriksson, Jari Lahti, Reiner Biffar, James F. Wilson, Luda Diatchenko, Jerome I. Rotter, Eric S. Orwoll, Launer J. Lenore, Cornelia M. van Duijn, Frances M K Williams, Munro Peacock, David A. Bennett, Annette Peters, Ali A. Aghdassi, Gudny Eiriksdottir, Weihua Zhang, Östen Ljunggren, Daniel L. Koller, Nicole Soranzo, Patricia A. Thompson, Jane A. Cauley, John A Robbins, Mattias Lorentzon, Igor Rudan, Thomas Illig, Claes Ohlsson, Ilja Demuth, Zoltán Kutalik, Aron S. Buchman, Jian'an Luan, Erik Ingelsson, Natalia Campos-Obando, Karol Estrada, Chan Soo Shin, Lisette Stolk, Gudmar Thorleifsson, Douglas P. Kiel, Michael N. Weedon, Lars Bertram, Fiona E. McGuigan, Ben A. Oostra, Thomas Meitinger, Mary F. Feitosa, Christian Gieger, Jean Wactawski-Wende, Yanhua Zhou, Serkalem Demissie, Najaf Amin, Anke W. Enneman, Håkan Melhus, Stuart H. Ralston, Johanna Kuusisto, Markku Laakso, Mark Walker, Tim D. Spector, Karl Michaëlsson, John-Olov Jansson, Richard L. Prince, Leif Mosekilde, Sabine Schipf, Carolina Medina-Gomez, Antti Jula, Carrie M. Nielson, Bente L. Langdahl, André G. Uitterlinden, Kay-Tee Khaw, Ruth J. F. Loos, Kristina Åkesson, Albert V. Smith, Tamara B. Harris, Cynthia A. Thomson, Karin M. A. Swart, Unnur Styrkarsdottir, Yi-Hsiang Hsu, Anne B. Newman, Murielle Bochud, M. Carola Zillikens, Alena Stančáková, Markus M. Lerch, Maria Nethander, Gregory Livshits, Dawn Waterworth, Christina M. Lill, Henry Völzke, Steven R. Cummings, Lise B. Husted, Cecilia M. Lindgren, Jaspal S. Kooner, Joshua R. Lewis, Katri Räikkönen, Linda Broer, Inês Barroso, Teemu Kuulasmaa, Jeffery R. O'Connell, Harald Grallert, William E. Kraus, Nicholas J. Wareham, Lars Lind, David Karasik, H-Erich Wichmann, Gregory J. Tranah, Mao Fu, Toby Johnson, Samuli Ripatti, Dan Mellström, Suzanne Satterfield, Jing Hua Zhao, Hyung Jin Choi, Vilmundur Gudnason, Lisette C. P. G. M. de Groot, Stephen B. Kritchevsky, Zhao Chen, Norman Klopp, Till Ittermann, Daniel S. Evans, Phillip L. De Jager, Ingrid B. Borecki, Laura M. Yerges-Armstrong, Peggy M. Cawthon, Thomas Lang, Markus Perola, Internal Medicine, Epidemiology, Clinical Genetics, General practice, APH - Societal Participation & Health, APH - Aging & Later Life, Epidemiology and Data Science, and APH - Personalized Medicine

Subjects
Adipose Tissue/metabolism, Male, 0301 basic medicine, Medicine (miscellaneous), Body Fluid Compartments/metabolism, Genome-wide association study, FTO gene, ADAMTS Proteins, Absorptiometry, Photon, Versicans, 0302 clinical medicine, Electric Impedance, European Continental Ancestry Group/genetics, Aged, 80 and over, 2. Zero hunger, Genetics, Extracellular Matrix Proteins, Nutrition and Dietetics, ADAMTS Proteins/genetics, RNA-Binding Proteins, Body Fluid Compartments, Middle Aged, metabolic profile, Nutritional Biology, body fat, Original Research Communications, Phenotype, Adipose Tissue, Body Composition, Receptor, Melanocortin, Type 4, Female, Bioelectrical impedance analysis, Adult, meta-analysis of genome-wide association studies, Versicans/genetics, Adolescent, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Biology, Extracellular Matrix Proteins/genetics, meta-Analysis of genome-wide association studies, Polymorphism, Single Nucleotide, White People, Young Adult, 03 medical and health sciences, Humans, Receptor, Melanocortin, Type 4/genetics, skeletal muscle, Allele, Muscle, Skeletal, VLAG, Aged, Global Nutrition, Wereldvoeding, Body Composition/genetics, body composition, Muscle, Skeletal/metabolism, 030109 nutrition & dietetics, Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics, RNA-Binding Proteins/genetics, Genetic architecture, Lean body mass, Genome-Wide Association Study
Abstract

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Published
2019

2. Plasma Metabolome Signature Indicative of BRCA1 Germline Status Independent of Cancer Incidence

Author

Judith Penkert, Andre Märtens, Martin Seifert, Bernd Auber, Katja Derlin, Ursula Hille-Betz, Philipp Hörmann, Norman Klopp, Jana Prokein, Lisa Schlicker, Frank Wacker, Hannah Wallaschek, Brigitte Schlegelberger, Karsten Hiller, Tim Ripperger, and Thomas Illig

Subjects
Cancer Research, DNA repair, Metabolite, Biology, lcsh:RC254-282, Germline, Malignant transformation, chemistry.chemical_compound, Breast cancer, breast cancer, energy metabolism, medicine, Metabolome, BRCA1 germline mutation, HIF1 alpha, aerobic glycolysis, Original Research, lactate, Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, NAD+ balance, plasma metabolome, chemistry, Oncology, Cancer cell, Cancer research
Abstract

Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (gBRCA1+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in gBRCA1+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 gBRCA1+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between gBRCA1+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in gBRCA1+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1-associated breast cancer.

Published
2021

3. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Inês Barroso, Gail Davies, H.-Erich Wichmann, Bjarke Feenstra, Peter Vollenweider, Nicholas J. Timpson, Alan F. Wright, Frank Geller, Gérard Waeber, John M. Starr, Benjamin M. Neale, George Davey Smith, Tõnu Esko, Ruth J. F. Loos, Andrew A. Hicks, Pedro Marques-Vidal, Dorret I. Boomsma, Harry Campbell, Zoltán Kutalik, David M. Evans, Scott D. Gordon, Eva Albrecht, Peter P. Pramstaller, Leena Peltonen, Jing Hua Zhao, Lavinia Paternoster, Thomas Hansen, Massimo Mangino, Fazil Aliev, Beate St Pourcain, Panos Deloukas, Heather A. Boyd, Guillaume Paré, Marco P. Boks, Monique M.B. Breteler, Jouke-Jan Hottenga, Xin Li, Kari Stefansson, Ian J. Deary, Jari Lahti, Inga Prokopenko, Nicholas Eriksson, Lili Milani, Nicholas J. Wareham, Jordan W. Smoller, Norman Klopp, Lynn Cherkas, Reedik Mägi, Margaret J. Wright, Peter Kraft, Jacques S. Beckmann, Brenda W.J.H. Penninx, Gabriel Cuellar-Partida, André G. Uitterlinden, Fernando Rivadeneira, Wendy L. McArdle, Johan G. Eriksson, Jiali Han, Jennifer E. Huffman, Andres Metspalu, J.M. Vink, Frank J. A. van Rooij, Christian Gieger, M. Arfan Ikram, Cecilia M. Lindgren, Aarno Palotie, Daniel I. Chasman, Joyce Y. Tung, Liang-Dar Hwang, David A. Hinds, Elisabeth Widen, Caroline Hayward, Michelle Luciano, Johannes H. Smit, Gonneke Willemsen, Dale R. Nyholt, Carolina Medina-Gomez, Nicole M. Warrington, Teemu Palviainen, Stacy Steinberg, Kay-Tee Khaw, Kevin S. O’Connell, Bettina Konte, Gudmar Thorleifsson, Eco J. C. de Geus, John P. Kemp, Mads Melbye, Mark I. McCarthy, Sarah E. Medland, Jaakko Kaprio, Cameron D. Palmer, Joel N. Hirschhorn, Ina Giegling, Scott Melville, Thomas Werge, Nicole Soranzo, Sigurdur H. Magnusson, Maris Teder-Laving, Hreinn Stefansson, Kauko Heikkilä, Cornelia M. van Duijn, David L. Duffy, Samuli Ripatti, Igor Rudan, Annette M. Hartmann, Ole A. Andreassen, Mari Nelis, Ozren Polasek, Vincent Mooser, Mousheng Xu, Eero Vuoksimaa, Katri Räikkönen, Nicholas G. Martin, Dan Rujescu, Tim D. Spector, Dawn M. Waterworth, Danielle M. Dick, Roel A. Ophoff, Epidemiology, Internal Medicine, Psychiatry, Biological Psychology, APH - Mental Health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Epidemiology and Data Science, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Pediatric surgery, and APH - Digital Health

Subjects
Male, Netherlands Twin Register (NTR), Linkage disequilibrium, Genome-wide association study, LANGUAGE DOMINANCE, Functional Laterality, Linkage Disequilibrium, Behavioral Neuroscience, 0302 clinical medicine, ddc:150, Gene Frequency, SCHIZOPHRENIA, Genetics, 0303 health sciences, Middle Aged, genetics [Genetic Variation], genetics [Functional Laterality], Schizophrenia, ASYMMETRY, genetics [Polymorphism, Single Nucleotide], Female, Adult, Social Psychology, LATERALIZATION, Experimental and Cognitive Psychology, genetics [Genetic Loci], Biology, Quantitative trait locus, Genetic correlation, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, LINKAGE ANALYSIS, METAANALYSIS, MICROTUBULE, AUTISM, ORIGINS, SCREEN, Quantitative Trait, Heritable, Sex Factors, Genetic linkage, medicine, Humans, Bipolar disorder, 030304 developmental biology, Genetic association study, Aged, Genetic Variation, medicine.disease, Genetic Loci, Autism, genetics [Gene Frequency], Developmental Psychopathology, 030217 neurology & neurosurgery, Neuroscience, Genome-Wide Association Study
Abstract

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Published
2021

4. Talin and vinculin are downregulated in atherosclerotic plaque; Tampere Vascular Study

Author

Norman Klopp, Pekka J. Karhunen, Magdaléna von Essen, Ivana Kholová, Vesa P. Hytönen, Thanos Sioris, Ari Mennander, Mika Kähönen, Terho Lehtimäki, Emma Raitoharju, Rolle Rahikainen, Niku Oksala, Thomas Illig, and Ilkka Seppälä

Subjects
Carotid Artery Diseases, Male, Talin, 0301 basic medicine, Pathology, medicine.medical_specialty, animal structures, Aortic Diseases, Down-Regulation, Fluorescent Antibody Technique, Lumen (anatomy), macromolecular substances, Vascular Remodeling, 030204 cardiovascular system & hematology, Polymerase Chain Reaction, Cell-Matrix Junctions, Focal adhesion, Peripheral Arterial Disease, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, medicine, Humans, Aorta, Abdominal, RNA, Messenger, Finland, Aged, Aged, 80 and over, Microscopy, Confocal, biology, Microarray analysis techniques, Middle Aged, Vinculin, Plaque, Atherosclerotic, Femoral Artery, Carotid Arteries, 030104 developmental biology, Case-Control Studies, biology.protein, Immunohistochemistry, Female, Cardiology and Cardiovascular Medicine, Intracellular, Homeostasis
Abstract

Background and aims Focal adhesions (FA) play an important role in the tissue remodeling and in the maintenance of tissue integrity and homeostasis. Talin and vinculin proteins are among the major constituents of FAs contributing to cellular well-being and intercellular communication. Methods Microarray analysis (MA) and qRT-PCR low-density array were implemented to analyze talin-1, talin-2, meta-vinculin and vinculin gene expression in circulating blood and arterial plaque. Results All analyzed genes were significantly and consistently downregulated in plaques (carotid, abdominal aortic and femoral regions) compared to left internal thoracic artery (LITA) control. The use of LITA samples as controls for arterial plaque samples was validated using immunohistochemistry by comparing LITA samples with healthy arterial samples from a cadaver. Even though the differences in expression levels between stable and unstable plaques were not statistically significant, we observed further negative tendency in the expression in unstable atherosclerotic plaques. The confocal tissue imaging revealed gradient of talin-1 expression in plaque with reduction close to the vessel lumen. Similar gradient was observed for talin-2 expression in LITA controls but was not detected in plaques. This suggests that impaired tissue mechanostability affects the tissue remodeling and healing capabilities leading to development of unstable plaques. Conclusions The central role of talin and vinculin in cell adhesions suggests that the disintegration of the tissue in atherosclerosis could be partially driven by downregulation of these genes, leading to loosening of cell-ECM interactions and remodeling of the tissue.

Published
2016

5. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Christian Gieger, Teemu Palviainen, Bettina Konte, Peter P. Pramstaller, Aarno Palotie, Elisabeth Widen, Monique M.B. Breteler, Caroline Hayward, Xin Li, Tim D. Spector, Jing Hua Zhao, John M. Starr, David M. Evans, Nicholas G. Martin, Wendy L. McArdle, Nicole Soranzo, Mads Melbye, Peter Kraft, André G. Uitterlinden, Beate St Pourcain, Massimo Mangino, Daniel I. Chasman, Jacques S. Beckmann, Gabriel Cuellar Partida, George Davey Smith, Cecilia M. Lindgren, Johan G. Eriksson, Alan F. Wright, Kauko Heikkilä, Eva Albrecht, Gudmar Thorleifsson, Mari Nelis, Nicholas Eriksson, Dawn M. Waterworth, Leena Peltonen, Frank J. A. van Rooij, Jari Lahti, Maris Teder-Laving, Igor Rudan, Annette M. Hartmann, Guillaume Paré, Ole A. Andreassen, Mohammad Arfan Ikram, Stacy Steinberg, Bjarke Feenstra, Peter Vollenweider, Sarah E. Medland, Brenda W.J.H. Penninx, Mark I. McCarthy, Jordan W. Smoller, Fazil Aliev, Joel N. Hirschhorn, Dan Rujescu, J.M. Vink, Dorret I. Boomsma, Harry Campbell, Pedro Marques-Vidal, David A. Hinds, Tõnu Esko, Ruth J. F. Loos, Zoltán Kutalik, Jouke-Jan Hottenga, Reedik Mägi, Dale R. Nyholt, Kari Stefansson, Kevin S. O’Connell, Hreinn Stefansson, Scott Melville, Andres Metspalu, Inês Barroso, Marco P. Boks, Gail Davies, Lavinia Paternoster, Thomas Hansen, Norman Klopp, H.-Erich Wichmann, David L. Duffy, Lili Milani, Heather A. Boyd, Michelle Luciano, Benjamin M. Neale, Margaret J. Wright, Fernando Rivadeneira, Liang-Dar Hwang, Scott D. Gordon, Jiali Han, Jennifer E. Huffman, Danielle M. Dick, Roel A. Ophoff, Ozren Polasek, Nicholas J. Wareham, Vincent Mooser, Mousheng Xu, Johannes H. Smit, Gonneke Willemsen, Ian J. Deary, Panos Deloukas, John P. Kemp, Cornelia M. van Duijn, Samuli Ripatti, Joyce Y. Tung, Eco J. C. de Geus, Cameron D. Palmer, Ina Giegling, Katri Räikkönen, Thomas Werge, Eero Vuoksimaa, Andrew A. Hicks, Inga Prokopenko, Lynn Cherkas, Sigurdur H. Magnusson, Gérard Waeber, Nicholas J. Timpson, Frank Geller, Carolina Medina-Gomez, Nicole M. Warrington, Kay-Tee Khaw, and Jaakko Kaprio

Subjects
Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Genetic variants, Biology, Association (psychology), Biobank, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Published
2019

6. Whole blood microRNA levels associate with glycemic status and correlate with target mRNAs in pathways important to type 2 diabetes

Author

Pashupati P. Mishra, Niku Oksala, Melanie Waldenberger, Ilkka Seppälä, Jaana Leiviskä, Reijo Laaksonen, Mika Kähönen, Markus Juonala, Nina Mononen, Olli T. Raitakari, Leo-Pekka Lyytikäinen, Thomas Illig, Norman Klopp, Emma Raitoharju, Nina Hutri-Kähönen, Britt-Marie Loo, Terho Lehtimäki, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, HUSLAB, Department of Diagnostics and Therapeutics, and University of Helsinki

Subjects
0301 basic medicine, Blood Glucose, endocrine system diseases, medicine.medical_treatment, lcsh:Medicine, Type 2 diabetes, DISEASE, GLUCOSE, MELLITUS, chemistry.chemical_compound, 0302 clinical medicine, Medicine, lcsh:Science, COMPLICATIONS, Multidisciplinary, PLASMA, biology, CARDIOVASCULAR RISK, miRNAs, Pre-diabetes, REGULATOR, medicine.medical_specialty, Biolääketieteet - Biomedicine, Article, DIFFERENTIAL EXPRESSION, 03 medical and health sciences, Insulin resistance, Diabetes mellitus, Internal medicine, Humans, RNA, Messenger, Glycemic, IDENTIFICATION, business.industry, Insulin, lcsh:R, medicine.disease, Impaired fasting glucose, Insulin receptor, MicroRNAs, 030104 developmental biology, Endocrinology, chemistry, Diabetes Mellitus, Type 2, POTENTIAL BIOMARKER, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, lcsh:Q, 3111 Biomedicine, Glycated hemoglobin, business, 030217 neurology & neurosurgery
Abstract

We analyzed the associations between whole blood microRNA profiles and the indices of glucose metabolism and impaired fasting glucose and examined whether the discovered microRNAs correlate with the expression of their mRNA targets. MicroRNA and gene expression profiling were performed for the Young Finns Study participants (n = 871). Glucose, insulin, and glycated hemoglobin (HbA1c) levels were measured, the insulin resistance index (HOMA2-IR) was calculated, and the glycemic status (normoglycemic [n = 534]/impaired fasting glucose [IFG] [n = 252]/type 2 diabetes [T2D] [n = 24]) determined. Levels of hsa-miR-144-5p, -122-5p, -148a-3p, -589-5p, and hsa-let-7a-5p associated with glycemic status. hsa-miR-144-5p and -148a-3p associated with glucose levels, while hsa-miR-144-5p, -122-5p, -184, and -339-3p associated with insulin levels and HOMA2-IR, and hsa-miR-148a-3p, -15b-3p, -93-3p, -146b-5p, -221-3p, -18a-3p, -642a-5p, and -181-2-3p associated with HbA1c levels. The targets of hsa-miR-146b-5p that correlated with its levels were enriched in inflammatory pathways, and the targets of hsa-miR-221-3p were enriched in insulin signaling and T2D pathways. These pathways showed indications of co-regulation by HbA1c-associated miRNAs. There were significant differences in the microRNA profiles associated with glucose, insulin, or HOMA-IR compared to those associated with HbA1c. The HbA1c-associated miRNAs also correlated with the expression of target mRNAs in pathways important to the development of T2D.

Published
2019

7. Kindlin 3 (FERMT3) is associated with unstable atherosclerotic plaques, anti-inflammatory type II macrophages and upregulation of beta-2 integrins in all major arterial beds

Author

Ilkka Seppälä, Mari Levula, Emma Raitoharju, Thanos Sioris, Mika Kähönen, Reijo Laaksonen, Thomas Illig, Niku Oksala, Norman Klopp, Vesa P. Hytönen, Jenita Pärssinen, Terho Lehtimäki, and Ivana Kholová

Subjects
Carotid Artery Diseases, Male, Pathology, medicine.medical_specialty, Microarray, Integrin, Aortic Diseases, Fluorescent Antibody Technique, Real-Time Polymerase Chain Reaction, FERMT3, Coronary artery disease, Downregulation and upregulation, medicine, Cluster Analysis, Humans, Aorta, Abdominal, Aged, Oligonucleotide Array Sequence Analysis, Whole blood, Aged, 80 and over, Inflammation, Rupture, Spontaneous, biology, Gene Expression Profiling, Macrophages, Membrane Proteins, Middle Aged, Atherosclerosis, medicine.disease, Thrombosis, Plaque, Atherosclerotic, Neoplasm Proteins, Up-Regulation, 3. Good health, Femoral Artery, Carotid Arteries, Phenotype, CD18 Antigens, Case-Control Studies, biology.protein, Immunohistochemistry, Female, Inflammation Mediators, Cardiology and Cardiovascular Medicine, Biomarkers
Abstract

Kindlins (FERMT) are cytoplasmic proteins required for integrin (ITG) activation, leukocyte transmigration, platelet aggregation and thrombosis. Characterization of kindlins and their association with atherosclerotic plaques in human(s) is lacking.Exploratory microarray (MA) was first performed followed by selective quantitative validation of robustly expressed genes with qRT-PCR low-density array (LDA). In LDA, ITGA1 (1.30-fold, p = 0.041) and ITGB3 (1.37-fold, p = 0.036) were upregulated in whole blood samples of patients with coronary artery disease (CAD) compared to healthy controls. In arterial plaques, both robustly expressed transcript variants of FERMT3 (MA: 5.90- and 3.4-fold; LDA: 3.99-fold, p0.0001 for all) and ITGB2 (MA: 4.81- and 4.92-fold; LDA: 5.29-fold, p0.0001 for all) were upregulated while FERMT2 was downregulated (MA: -1.61-fold; LDA: -2.88-fold, p0.0001 for both). The other integrins (ITGA1, ITGAV, ITGB3, ITGB5) were downregulated. All these results were replicated in at least one arterial bed. The latter FERMT3 transcript variant associated with unstable plaques (p = 0.0004). FERMT3 correlated with M2 macrophage markers and in hierarchical cluster analysis clustered with inflammatory and macrophage markers, while FERMT2 correlated with SMC-rich plaque markers and clustered with SMC markers. In confocal immunofluorescence analysis, FERMT3 protein colocalized with abundant CD68-positive cells of monocytic origin in the atherosclerotic plaques, while co-localization of FERMT3 with HHF35 indicative of smooth muscle cells was low.Kindlin-3 (FERMT3) is upregulated in atherosclerotic, especially unstable plaques, mainly in cells of monocytic origin and of M2 type. Simultaneous upregulation of ITGB2 suggests a synergistic effect on leukocyte adherence and transmigration into the vessel wall.

Published
2015

8. Differentially expressed genes and canonical pathways in the ascending thoracic aortic aneurysm – The Tampere Vascular Study

Author

Miska Sulkava, Mari Levula, Mika Kähönen, Ari Mennander, Norman Klopp, Otso Järvinen, Nina Mononen, Niku Oksala, Thomas Illig, Ilkka Seppälä, Reijo Laaksonen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, and Emma Raitoharju

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_specialty, lcsh:Medicine, Aorta, Thoracic, 030204 cardiovascular system & hematology, Biology, Thoracic aortic aneurysm, Article, Transcriptome, 03 medical and health sciences, Aortic aneurysm, 0302 clinical medicine, medicine.artery, medicine, Humans, Aortic rupture, Hox gene, lcsh:Science, Aged, Aorta, Multidisciplinary, Aortic Aneurysm, Thoracic, lcsh:R, Middle Aged, medicine.disease, Fold change, 3. Good health, 030104 developmental biology, Gene Ontology, Homeobox, lcsh:Q, Female, Signal Transduction
Abstract

Ascending thoracic aortic aneurysm (ATAA) is a multifactorial disease with a strong inflammatory component. Surgery is often required to prevent aortic rupture and dissection. We performed gene expression analysis (Illumina HumanHT-12 version 3 Expression BeadChip) for 32 samples from ATAA (26 without/6 with dissection), and 28 left internal thoracic arteries (controls) collected in Tampere Vascular study. We compared expression profiles and conducted pathway analysis using Ingenuity Pathway Analysis (IPA) to reveal differences between ATAA and a healthy artery wall. Almost 5000 genes were differentially expressed in ATAA samples compared to controls. The most downregulated gene was homeobox (HOX) A5 (fold change, FC = −25.3) and upregulated cadherin-2 (FC = 12.6). Several other HOX genes were also found downregulated (FCs between -25.3 and -1.5, FDR

Published
2017

9. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author

Rob M. van Dam, Francis S. Collins, Konstantin Strauch, Raimund Erbel, Rafn Benediktsson, Philippe Froguel, Kyle J. Gaulton, Peter Donnelly, Torben Hansen, Longda Jiang, Lennart C. Karssen, Rona J. Strawbridge, David J. Hunter, Leena Kinnunen, Thomas Meitinger, Michael Stumvoll, Stéphane Cauchi, Ching-Ti Liu, Olga McLeod, Oluf Pedersen, Michael Boehnke, Denis Rybin, Karl Gertow, Tõnu Esko, Bernhard O. Boehm, Sonali Pechlivanis, Bo Isomaa, Anne U. Jackson, Clement Ma, Yingchang Lu, Nicola D. Kerrison, Ruth J. F. Loos, Caroline S. Fox, Chiara Scapoli, Jian'an Luan, Martina Müller-Nurasyid, Domenico Palli, Anke Tönjes, Natalie R. van Zuydam, Neil Robertson, Barbara Thorand, Natalia Pervjakova, Andrew R. Wood, Karin Leander, Unnur Thorsteinsdottir, Sara M. Willems, Karen L. Mohlke, Robert A. Scott, Markus M. Nöthen, Ulf de Faire, Qi Sun, Eric Boerwinkle, Roman Wennauer, Douglas M. Ruderfer, Marika Kaakinen, Nigel W. Rayner, Jaakko Tuomilehto, Nisa M. Maruthur, Richard N. Bergman, Janina S. Ried, Himanshu Chheda, Josée Dupuis, Juan Tajes-Fernandes, Steve E. Humphries, Reedik Mägi, Gonçalo R. Abecasis, B F Voight, David Couper, Cornelia M. van Duijn, Samuli Ripatti, Yeji Lee, Heikki A. Koistinen, Christian Dina, Andres Metspalu, Lu Qi, James S. Pankow, Han Chen, Damiano Baldassarre, Mattias Frånberg, Gerald Steinbach, Inga Prokopenko, Matthias Blüher, Jose C. Florez, Julia Meyer, Niels Grarup, Anders Hamsten, Valeriya Lyssenko, James B. Meigs, Pritam Chanda, Leif Groop, Sarah Edkins, Anubha Mahajan, Gunnar Sigurðsson, Marilyn C. Cornelis, Christian Gieger, Nancy L. Pedersen, Andrew T. Hattersley, Paul W. Franks, Nicholas J. Wareham, Stefan Gustafsson, Katharine R. Owen, Peter Kovacs, Andrew D. Johnson, Lori L. Bonnycastle, Tiinamaija Tuomi, Aurelio Barricarte Gurrea, Tune H. Pers, Eric J.G. Sijbrands, Phoenix Kwan, Emmi Tikkanen, Elisabeth M. van Leeuwen, Stéphane Lobbens, Claudia Langenberg, E. Eury, Thomas W. Mühleisen, Lewin Eisele, Veikko Salomaa, Satu Mӓnnistö, Christian Fuchsberger, Evelin Mihailov, David Altshuler, Timothy M. Frayling, Peter Almgren, Harald Grallert, Hans A. Kestler, Beverley Balkau, Erik Ingelsson, Colin N. A. Palmer, Yvonne T. van der Schouw, Michael Roden, Thomas Sparsø, Karl-Heinz Jöckel, Johan G. Eriksson, Inês Barroso, John D. Eicher, Bengt Sennblad, Bruna Gigante, Andrew D. Morris, Panagiotis Deloukas, Man Li, Allan Linneberg, Astradur B. Hreidarsson, Lars Lannfelt, Elena Tremoli, Liming Liang, Omri Gottesman, Letizia Marullo, Peter S. Chines, Kari Stefansson, Mark I. McCarthy, Andrew P. Morris, Erwin P. Bottinger, Augustine Kong, Torben Jørgensen, Tanya M. Teslovich, Frank B. Hu, Dorothée Thuillier, Peter Kraft, Heiner Boeing, Laura J. Scott, Gudmar Thorleifsson, Lars Lind, John R. B. Perry, Heather M. Stringham, Susanne Moebus, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Guillaume Charpentier, Eleftheria Zeggini, Leena Peltonen, Loic Yengo, Norman Klopp, Teresa Ferreira, Christian Theil Have, Marit E. Jørgensen, Epidemiology, Erasmus MC other, Internal Medicine, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Commission of the European Communities, and Wellcome Trust

Subjects
PROVIDES, 0301 basic medicine, SUSCEPTIBILITY LOCI, endocrine system diseases, Endocrinology, Diabetes and Metabolism, PATHOPHYSIOLOGY, European Continental Ancestry Group, Medizin, Genome-wide association study, Biology, Quantitative trait locus, Bioinformatics, White People, GENETIC ARCHITECTURE, NO, Endocrinology & Metabolism, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Diabetes Mellitus, Internal Medicine, Journal Article, Glucose homeostasis, Humans, 1000 Genomes Project, Allele frequency, METAANALYSIS, 11 Medical and Health Sciences, RISK, Genetics, Science & Technology, RECEPTOR, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Haplotype, Genetic Variation, nutritional and metabolic diseases, Genetic architecture, 030104 developmental biology, Diabetes Mellitus, Type 2, Gene Expression Regulation, RARE VARIANTS, LOW-FREQUENCY, Life Sciences & Biomedicine, Type 2, 030217 neurology & neurosurgery, Imputation (genetics), FASTING GLUCOSE, Genome-Wide Association Study
Abstract

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

Published
2017

10. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author

Jing Hua Zhao, Hyung Jin Choi, Leslie J. Baier, Vilmundur Gudnason, Melina Claussnitzer, Jian Shen, Mary F. Feitosa, Melissa E. Garcia, Douglas P. Kiel, Murielle Bochud, Christian Gieger, L. B. Husted, Kristina Åkesson, Alan Hubbard, John-Olov Jansson, Jacqueline S. L. Kloth, Yanhua Zhou, Richard L. Prince, Angela Döring, H.-Erich Wichmann, Thomas Girke, Monica J. Hubal, Mark A. Tarnopolsky, Laura M. Yerges-Armstrong, Yi-Hsiang Hsu, Patricia A. Thompson, Mattias Lorentzon, Gudmar Thorleifsson, Wen-Chi Chou, Karin M. A. Swart, Tim D. Spector, Braxton D. Mitchell, Kim M. Huffman, Inês Barroso, Igor Rudan, William E. Kraus, Nicholas J. Wareham, Chan Soo Shin, Jaakko Tuomilehto, Gunnar Sigurdsson, Bok Ghee Han, Munro Peacock, Mao Fu, Unnur Thorsteinsdottir, Gregory Livshits, Laura J. Scott, Jane A. Cauley, Heikki A. Koistinen, Arjun Verma, Peggy M. Cawthon, Carrie M. Nielson, Aron S. Buchman, Aarno Palotie, Daniel S. Evans, Elisabeth Widen, Caroline Hayward, Frances M K Williams, Nam H. Cho, Peter Vollenweider, Liisa Byberg, Robert Luben, Veikko Salomaa, Alena Stančáková, Markus M. Lerch, Jian'an Luan, Eric P. Hoffman, Thomas Lang, Jari Lahti, Mike Erdos, Stephen C. J. Parker, Ida Malkin, Jaspal S. Kooner, Francis S. Collins, Claes Ohlsson, James F. Wilson, Ben A. Oostra, Carolina Medina-Gomez, Toby Johnson, Cornelia M. van Duijn, Joel Eriksson, Natalia Campos Obanda, Samuli Ripatti, Kay-Tee Khaw, Ryan P. Welch, Jeffrey R. O'Connell, Karl Michaëlsson, Erik Ingelsson, Elizabeth A. Streeten, Eric E. Schadt, Markus Perola, Albert V. Smith, Henna Cederberg, Ruth J. F. Loos, Michael J. Econs, Thomas Illig, Ingrid B. Borecki, Unnur Styrkarsdottir, Kari Stefansson, Anne B. Newman, Ozren Polasek, Weihua Zhang, Shad B. Smith, Wen Chi Hsueh, Serkalem Demissie, Najaf Amin, Simon Melov, Lenore J. Launer, Harald Grallert, E. Steinhagen-Thiessen, Jean Wactawski-Wende, Stuart H. Ralston, Leif Mosekilde, Liesbeth Vandenput, Zoltán Kutalik, Nicole L. Glazer, Teemu Kuulasmaa, Lisette Stolk, Johanna Kuusisto, Lei Yu, Steven R. Cummings, Cynthia A. Thomson, Harry Campbell, Mark Walker, Lars Lind, André G. Uitterlinden, Albert Hofman, Linda Broer, Vicky Ossowski, John C. Chambers, Jerome I. Rotter, Gregory J. Tranah, Östen Ljunggren, Tamara B. Harris, Ali A. Aghdassi, Nicole Soranzo, Jong-Young Lee, Bruce M. Psaty, Magnus Karlsson, Luda Diatchenko, Nicole C. Wright, A.W. Enneman, Cecilia M. Lindgren, Yongmei Liu, Sabine Schipf, Tian Liu, Annette Peters, Daniel L. Koller, Georg Homuth, Ilja Demuth, Andrew P. Morris, Jagvir Grewal, Katri Räikkönen, Markku Laakso, Tuomas O. Kilpeläinen, Michael Boehnke, Fernando Rivadeneira, David A. Bennett, Joban Sehmi, Gudny Eiriksdottir, Rainer Biffar, Till Ittermann, Natasja M. van Schoor, Michael N. Weedon, Zhao Chen, Norman Klopp, Antti Jula, Bente L. Langdahl, William Maixner, Håkan Melhus, Rosalie A. M. Dhonukshe-Rutten, Dan Mellström, Robert L. Hanson, M. Carola Zillikens, Janina S. Ried, David Karasik, Suzanne Satterfield, Stephen B. Kritchevsky, Henry Völzke, Karol Estrada, Thomas Meitinger, Sian Tsung Tan, John A Robbins, Dawn M. Waterworth, Lars Bertram, Fiona E. McGuigan, Philip L. De Jager, Youfang Liu, Emmi Tikkanen, Eric S. Orwoll, Weijia Xie, Joanne M. Jordan, Johan G. Eriksson, Joshua R. Lewis, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, School of Medicine / Clinical Medicine, Internal Medicine, Epidemiology, Clinical Genetics, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Luben, Robert [0000-0002-5088-6343], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Societal Participation & Health, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, Epidemiology and Data Science, APH - Personalized Medicine, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Department of Medicine, Endokrinologian yksikkö, Medicum, Department of Psychology and Logopedics, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Department of Medical and Clinical Genetics, Quantitative Genetics, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, and Genomic Discoveries and Clinical Translation

Subjects
0301 basic medicine, Medicin och hälsovetenskap, 17-Hydroxysteroid Dehydrogenases, General Physics and Astronomy, Physiology, Genome-wide association study, VARIANTS, Bioinformatics, Medical and Health Sciences, Genome-wide association studies, 0302 clinical medicine, ADAMTS Proteins, Versicans, Regulatory Elements, Transcriptional, GENE-EXPRESSION, INSULIN-RESISTANCE, Extracellular Matrix Proteins, Multidisciplinary, Aldehyde Oxidoreductases, Multidisciplinary Sciences, Phenotype, OBESITY, Body Composition, Science & Technology - Other Topics, Medical genetics, BONE-MINERAL DENSITY, PHYSICAL-DISABILITY, Bioelectrical impedance analysis, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, medicine.medical_specialty, Science, Quantitative Trait Loci, UNITED-STATES, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Biology, Predictive markers, Polymorphism, Single Nucleotide, SARCOPENIA, General Biochemistry, Genetics and Molecular Biology, SKELETAL-MUSCLE MASS, 03 medical and health sciences, Insulin resistance, Thinness, MD Multidisciplinary, Journal Article, medicine, Humans, Life Science, Erfðafræði, Human height, Science & Technology, predictive markers, General Chemistry, Rannsóknir, Líkamsvöxtur, Arfgengi, medicine.disease, Obesity, Onderwijsinstituut, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Sarcopenia, genome-wide association studies, Lean body mass, Insulin Receptor Substrate Proteins, gene expression, Gene expression, HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p, We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland’s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI’s Atherosclerosis Risk in Communities (ARIC) Study, and Iceland’s Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik): has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Old Order Amish (OOA): this work was supported by NIH research grants U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, and U01 HL084756. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488).). L.M.Y.-A. was supported by F32AR059469 from NIH/NIAMS. M.F. was supported by American Heart Association grant 10SDG2690004. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CoLaus: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). We thank Vincent Mooser and Gérard Waeber, Co-PIs of the CoLaus study. Special thanks to Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. Data analysis was supervised by Sven Bergmann and Jacques S. Beckmann. The computations for this paper were performed in part at the Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. The EPIC Study: The EPIC Obesity study is funded by Cancer Research United Kingdom and the Medical Research Council. I.B. acknowledges support from EU FP6 funding (contract no. LSHM-CT-2003-503041) and by the Wellcome Trust (WT098051). Erasmus Rucphen Family (ERF) Study: The study was supported by grants from The Netherlands Organisation for Scientific Research (NWO), Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. We are grateful to all general practitioners for their contributions, to Petra Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and Peter Snijders for his help in data collection. Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF—1333-00124 and Sapere Aude program grant DFF—1331-00730B). Framingham Osteoporosis Study (FOS)/Framingham Heart Study (FHS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and U24AG051129; D.P.K. and R01AR057118; D.K. D.K. was also supported by FP7-PEOPLE-2012-Marie Curie Career Integration Grants (CIG)). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, and the Göteborg Medical Society. We would like to thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015G for access to their grid resources. We also thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands for advice regarding the grid resources. Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG 041517 and M01 RR-00750. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Kora (KORA F3 and KORA F4): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The London Life Sciences Population (LOLIPOP): The study was funded by the British Heart Foundation, Wellcome Trust, the Medical Research Council, and Kidney Research UK. The study also receives support from a National Institute for Health Research (NIHR) programme grant. Rotterdam Study (RSI, RSII & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, PhD, for the creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Karol Estrada, Dr Fernando Rivadeneira, Dr Tobias A. Knoch, Anis Abuseiris, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP, and we thank BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015G) for access to their grid computing resources. Rush Memory and Aging Project (MAP): The Memory and Aging Project was supported by National Institute on Aging grants R01AG17917, R01AG15819, and R01AG24480, the Illinois Department of Public Health, the Rush Clinical Translational Science Consortium, and a gift from Ms Marsha Dowd. TwinsUK (TUK): The study was funded by the Wellcome Trust, Arthritis Research UK, and the Chronic Disease Research Foundation. The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff and volunteers of the TwinsUK study. The study was also supported by Israel Science Foundation, grant number 994/10. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Berlin Aging Study II (BASE-II) was supported by the German Federal Ministry of Education and Research (BMBF (grants #16SV5536K, #16SV5537, #16SV5538, and #16SV5837; previously #01UW0808)). Additional contributions (e.g., financial, equipment, logistics, personnel) are made from each of the other participating sites, i.e., the Max Planck Institute for Human Development (MPIB), Max Planck Institute for Molecular Genetics (MPIMG), Charite University Medicine, German Institute for Economic Research (DIW), all located in Berlin, Germany, and University of Lübeck in Lübeck, Germany. B-vitamins in the prevention of osteoporotic fractures (B-PROOF): B-PROOF is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam. All organizations are based in the Netherlands. We thank Dr Tobias A. Knoch, Anis Abuseiris, Karol Estrada, and Rob de Graaf as well as their institutions the Erasmus Grid Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology (grants #01 AK 803 A-H and #01 IG 07015G) for access to their gird resources. Further, we gratefully thank all participants. Calcium Intake Fracture Outcome Study (CAIFOS): This study was funded by Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grants (254627, 303169, and 572604). We are grateful to the participants of the CAIFOS Study. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship. Danish Osteoporosis Study (DOPS): The study was supported by Karen Elise Jensen foundation. Family Heart Study (FamHS): The study was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from NHLBI; and R01-DK-089256 and R01-DK-075681 from NIDDK. GenMets (Health 2000): S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. S.M. was supported by grants #136895 and #141005, V.S. by grants #139635 and 129494, and M.P. by grant #269517 from the Academy of Finland and a grant from the Finnish Foundation for Cardiovascular Research. M.P. was supported by the Yrjö Jahnsson Foundation. Helsinki Birth Cohort Study (HBCS): We thank all study participants as well as everybody involved in the HBCS. HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Samfundet Folkhälsann, Novo Nordisk Foundation, Liv och Hälsa, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). Johnston County Study: The Johnston County Osteoarthritis Project is supported in part by cooperative agreements S043, S1734, and S3486 from the Centers for Disease Control and Prevention/Association of Schools of Public Health; the NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant 5-P60-AR30701; and the NIAMS Multidisciplinary Clinical Research Center grant 5 P60 AR49465-03. Genotyping services were provided by Algynomics company. Korean Genome Epidemiology Study (KoGES): Korean Genome Epidemiology Study (KoGES): This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (found 2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00). Kora F3 and Kora F4: The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. LOLIP-REP-IA610: The study was supported by the Wellcome Trust. We thank the participants and research teams involved in LOLIPOP. LOLIP-REP-IA_I: The study was supported by the British Heart Foundation Grant SP/04/002. LOLIP-REP-IA_P: The study was supported by the British Heart Foundation Grant SP/04/002. METSIM: The study was supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and the EVO grant 5263 from the Kuopio University Hospital. MrOS Sweden: Financial support was received from the Swedish Research Council (2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Novo Nordisk foundation. Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. MrOS US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Orkney Complex Disease Study (ORCADES): ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK (17539) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PEAK 25: This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS): The study was supported by grants from the Swedish research council (projects 2008-2202 and 2005-8214) and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC): The RISC study is supported by European Union Grant QLG1-CT-2001-01252 and AstraZeneca. We thank Merck Research Labs for conducting DNA genotyping on RISC samples.Rotterdam III: Rotterdam Study (RS): See discovery. SHIP and SHIP TREND: This work was supported by SHIP, which is part of the Community Medicine Research Network of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens. A.G. and the Cache´ Campus program of the InterSystems GmbH. The SHIP authors are grateful to the contribution of Florian Ernst, Anja Wiechert, and Astrid Petersmann in generating the SNP data and to Mario Stanke for the opportunity to use his Server Cluster for SNP Imputation. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-1) and the Federal Ministry of Nutrition, Agriculture and Consumer’s Safety. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Uppsala Longitudinal Study of Adult Men (ULSAM): The study was funded by grants from the Swedish research council (projects 2008-2202 and 2005-8214), the Wallenberg foundation, and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, grant number WT098017. CROATIA-VIS (VIS): The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). We acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Women’s Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. FUSION: This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank all the subjects for participation and the study personnel for excellent technical assistance. The Pima Indian Study: This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA. Studies of a Targeted Risk Reduction Intervention with Defined Exercise (STRRIDE): This study was supported by the National Heart Lung and Blood Institute of the National Institutes of Health, HL57453 (WEK). Gene expression in old and young muscle biopsies: S.M. and T.G. were supported in part by NIH U24AG051129.

Published
2017

11. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author

Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. Hanis, Thomas WMühleisen, Congrong Wang, Sonia Shah, Kyle J. Gaulton, Jaspal S. Kooner, Jiro Nakamura, Mustafa Atalay, Linda S. Adair, S Wiltshire, Tõnu Esko, Anna Jonsson, Antigone S. Dimas, Karin Leander, Li Ching Chang, George B. Grant, Bo Isomaa, Anne U. Jackson, Claudia Langenberg, Kristian Hveem, Yoon Shin Cho, Astradur B. Hreidarsson, Xu Wang, Keizo Ohnaka, Alexandra C. Nica, Simon D. Rees, Pau Navarro, Sekar Kathiresan, Rob M. van Dam, Zafar I. Hydrie, Bok Ghee Han, Francis S. Collins, Fuu Jen Tsai, Unnur Thorsteinsdottir, Ross M. Fraser, Caroline Hayward, Cornelia M. van Duijn, Samuli Ripatti, Mieke D. Trip, Hyung Lae Kim, Rafn Benediktsson, Candace Guiducci, Bruna Gigante, Kyong Soo Park, Wen Hong L. Kao, Tom Wilsgaard, Leena Kinnunen, John Danesh, Alan James, Alan R. Shuldiner, Mitsuhiro Yokota, Jen Mai Lee, Kari Stefansson, Erik Ingelsson, Colin N. A. Palmer, David J. Hunter, Paul Zimmet, Manickam Chidambaram, Sirkka Keinänen-Kiukaanniemi, Laura J. Scott, Susanne Moebus, Benjamin F. Voight, Wolfgang Rathmann, Hassan Khan, Thomas Illig, Prasad Katulanda, Christian Gieger, Andrew D. Morris, Yik Ying Teo, Andrew P. Morris, Venkatesan Radha, N. William Rayner, Johan G. Eriksson, Christian Dina, Igor Rudan, Sailaja Vedantam, Cheng Hu, James S. Pankow, Ann-Christine Syvänen, Karl Gertow, Valeriya Lyssenko, Guillaume Charpentier, Albert Hofman, Chiea Chuen Khor, Joseph Trakalo, Peter Kraft, Takashi Kadowaki, Qiuyin Cai, John C. Chambers, André G. Uitterlinden, Simon C. Potter, Nicholas J. Wareham, Soumya Raychaudhuri, Jian'an Luan, Tiinamaija Tuomi, Anthony H. Barnett, Juha Saltevo, Robert A. Scott, Valgerdur Steinthorsdottir, Peng Keat Ng, Mark I. McCarthy, Åsa K. Hedman, Kerrin S. Small, Julia Meyer, Frank B. Hu, Cecilia M. Lindgren, Jennifer E. Below, Nancy J. Cox, Jennie Hui, Andrew Crenshaw, Latonya F. Been, Nam H. Cho, Janani Pinidiyapathirage, A. Samad Shera, Bernhard OBoehm, Jason Carey, Augustine Kong, Twee Hee Ong, Philippe M. Frossard, Donald W. Bowden, Toshimasa Yamauchi, Steve E. Humphries, Cordelia Langford, Xinzhong Li, Hiroshi Ikegami, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Debashish Das, John Beilby, Robin Young, Christian Herder, Asif Rasheed, Neil Robertson, Raimund Erbel, Fumihiko Takeuchi, Markku Laakso, Esteban J. Parra, Panos Deloukas, Eric Boerwinkle, Adan Valladares-Salgado, Chien-Hsiun Chen, Kay-Tee Khaw, Damiano Baldassarre, Ashok Kumar, E. Shyong Tai, Peter S. 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Uppsala Hosp, Dept Mol Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 122 ] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan [ 123 ] Dept Social Serv & Hlth Care, Pietarsaari, Finland [ 124 ] Aga Khan Univ, Dept Med, Karachi, Pakistan [ 125 ] Queen Elizabeth II Med Ctr, West Australian Sleep Disorders Res Inst, Dept Pulm Physiol & Sleep Med, Nedlands, WA, Australia [ 126 ] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia [ 127 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 128 ] Heart & Diabet Inst, Baker Int Diabet Inst IDI, Melbourne, Australia [ 129 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 130 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 131 ] Natl Ctr Global Hlth & Med, Res Inst, Shinjuku Ku, Tokyo, Japan [ 132 ] Univ Colombo, Dept Clin Med, Diabet Res Unit, Colombo, Sri Lanka [ 133 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 134 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 135 ] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore [ 136 ] Ewha Womans Univ, Sch Med, Dept Biochem, Seoul, South Korea [ 137 ] Soongsil Univ, Sch Syst Biomed Sci, Seoul, South Korea [ 138 ] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland [ 139 ] deCODE Genet, Reykjavik, Iceland [ 140 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 141 ] Minist Hlth, Port Louis, Mauritius [ 142 ] Univ Toronto, Dept Anthropol, Mississauga, ON L5L 1C6, Canada [ 143 ] Fdn IMSS, Mexico City, DF, Mexico [ 144 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 145 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 146 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 147 ] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Nedlands, WA 6009, Australia [ 148 ] Univ San Carlos, Off Populat Studies Fdn Inc, Cebu, Philippines [ 149 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England [ 150 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 151 ] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA [ 152 ] Beijing Genom Inst, Shenzhen, Peoples R China [ 153 ] Uppsala Univ, Akad Sjukhuset, Dept Med Sci, Uppsala, Sweden [ 154 ] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA [ 155 ] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA [ 156 ] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA [ 157 ] Shanghai Inst Prevent Med, Shanghai, Peoples R China [ 158 ] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA [ 159 ] Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India [ 160 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 161 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 162 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany [ 163 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 164 ] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia [ 165 ] Nagoya Univ, Grad Sch Med, Div Endocrinol & Diabet, Dept Internal Med, Nagoya, Aichi 4648601, Japan [ 166 ] Chubu Rosai Hosp, Dept Endocrinol & Diabet, Nagoya, Aichi, Japan [ 167 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 168 ] Kyushu Univ, Grad Sch Med Sci, Dept Geriatr Med, Higashi Ku, Fukuoka 812, Japan [ 169 ] Churchill Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford OX3 7LJ, England [ 170 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 171 ] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, World Class Univ Program, Seoul, South Korea [ 172 ] Seoul Natl Univ, Coll Med, Seoul, South Korea [ 173 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 174 ] Inst Mol Med Finland FIMM, Helsinki, Finland [ 175 ] Helmholtz Zentrum Muenchen, Inst Epidemiol 2, Neuherberg, Germany [ 176 ] Univ Kelaniya, Fac Med, Dept Publ Hlth, Ragama, Sri Lanka [ 177 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 178 ] Univ Gen Hosp Attikon, Athens, Greece [ 179 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany [ 180 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 181 ] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA [ 182 ] Partners Ctr Personalized Genom Med, Boston, MA USA [ 183 ] Univ Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 184 ] Univ Dusseldorf, Dept Metab Dis, Dusseldorf, Germany [ 185 ] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA [ 186 ] MIT, Boston, MA USA [ 187 ] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA [ 188 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 189 ] Finnish Diabet Assoc, Tampere, Finland [ 190 ] Pirkanmaa Hosp Dist, Tampere, Finland [ 191 ] Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland [ 192 ] South Karelia Cent Hosp, Lappeenranta, Finland [ 193 ] UCL, Dept Genet Evolut & Environm, Genet Inst, London, England [ 194 ] Diabet Assoc Pakistan, Karachi, Pakistan [ 195 ] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA [ 196 ] Baltimore Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA [ 197 ] Univ Maryland, Sch Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA [ 198 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 199 ] Univ Ulm, Dept Clin Chem, D-89069 Ulm, Germany [ 200 ] Univ Ulm, Cent Lab, D-89069 Ulm, Germany [ 201 ] Uppsala Univ, Dept Med Sci, Uppsala, Sweden [ 202 ] Kyushu Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan [ 203 ] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland [ 204 ] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain [ 205 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 206 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 207 ] IMSS, Ctr Med Nacl Siglo 21, Hosp Especialidades, Unidad Invest Med Bioquim, Mexico City, DF, Mexico [ 208 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 209 ] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia [ 210 ] Kyushu Univ, Med Inst Bioregulat, Res Ctr Genet Informat, Div Genome Anal,Higashi Ku, Fukuoka 812, Japan [ 211 ] Univ Lille 1, Math Lab, CNRS UMR 8524, MODAL Team,INRIA Lille Nord Europe, F-59655 Villeneuve Dascq, France [ 212 ] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan [ 213 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 214 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 215 ] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA [ 216 ] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA [ 217 ] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA [ 218 ] Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea [ 219 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 220 ] Imperial Coll Healthcare NHS Trust, London, England [ 221 ] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA [ 222 ] Blood Syst Res Inst, San Francisco, CA USA [ 223 ] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore [ 224 ] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore [ 225 ] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore [ 226 ] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore [ 227 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Surgery, Epidemiology, Dermatology, Internal Medicine, Medical Microbiology & Infectious Diseases, Medical Research Council (MRC), National Institute for Health Research, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology

Subjects
CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

Published
2014

12. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author

Richard S. Cooper, Angela Döring, Cisca Wijmenga, Jerome I. Rotter, Linda S. Adair, Tõnu Esko, Jennifer L. Bragg-Gresham, Danish Saleheen, Narisu Narisu, Xiaohui Li, Kathleen Stirrups, Ulf de Faire, Nicholas G. Martin, Dmitry Shungin, Peter Vollenweider, Yii-Der Ida Chen, Dharambir K. Sanghera, George Dedoussis, Toshiko Tanaka, Manjinder S. Sandhu, Anne U. Jackson, Nancy L. Pedersen, Maria Dimitriou, Shih-Yi Lin, David P. Strachan, Isleifur Olafsson, Ruth J. F. Loos, Kay-Tee Khaw, Antero Kesäniemi, Rainer Rauramaa, Wendy L. McArdle, Gonneke Willemsen, Dena G. Hernandez, May E. Montasser, Amy J. Swift, Colin A. McKenzie, Aaron Isaacs, Latonya F. Been, Leif Groop, Massimo Mangino, Martina Müller-Nurasyid, Karen L. Mohlke, Ci Song, Sailaja Vedantam, Anna-Liisa Hartikainen, Lori L. Bonnycastle, Ilja M. Nolte, Jaakko Kaprio, Anneli Pouta, Unnur Thorsteinsdottir, Paul Elliott, Muredach P. Reilly, Jean Ferrières, Daniel J. Rader, Elizabeth H. Young, Jaspal S. Kooner, Leena Moilanen, Markku Laakso, Albert Hofman, Kelly A. Volcik, Sekar Kathiresan, Tamara B. Harris, Eric Kim, Aimo Ruokonen, Andrea Ganna, Serena Sanna, John J.P. Kastelein, Martha L. Gravito, Ronald M. Krauss, Ken K. Ong, Paul M. Ridker, Kristian Hveem, Ayse Demirkan, Alena Stančáková, Pierre Meneton, Thomas Quertermous, John Danesh, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Christopher J. Groves, Jaakko Tuomilehto, Michael Boehnke, Jose M. Ordovas, Alan B. Feranil, Chao A. Hsiung, Wayne Huey-Herng Sheu, Igor Rudan, Christa Meisinger, Rebecca N. Nsubuga, Bruna Gigante, Inger Njølstad, Göran Hallmans, Aroon D. Hingorani, Jouko Saramies, Deepti Gurdasani, Fernando Rivadeneira, Andres Metspalu, Stephen E. Epstein, Gonçalo R. Abecasis, Braxton D. Mitchell, Devin Absher, Marcus E. Kleber, Sonia Shah, Pierre Fontanillas, Jeffrey R. O'Connell, Louise A. Donnelly, Jing Hua Zhao, Martin L. Buchkovich, Francis S. Collins, Gabrielle Müller, Matti Uusitupa, Evelin Mihailov, Nicholas J. Wareham, Andrew A. Hicks, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Jaana Lindström, Mark I. McCarthy, Evita G. Van Den Herik, Kirsten Ohm Kyvik, Vilmundur Gudnason, Jackie F. Price, Joel N. Hirschhorn, Winfried März, Aravinda Chakravarti, Pontiano Kaleebu, James F. Wilson, Lindsay L. Waite, Leo-Pekka Lyytikäinen, Sebanti Sengupta, Mika Kivimäki, David Altshuler, Hilma Holm, Rona J. Strawbridge, Harald Grallert, Ramaiah Nagaraja, Laurence Tiret, G. Kees Hovingh, Meena Kumari, Nilesh J. Samani, Daniel F. Freitag, Nelson B. Freimer, Thomas Illig, Panos Deloukas, Bernhard O. Boehm, Nicholas W.J. Wainwright, Mark J. Daly, Mika Kähönen, Michel Burnier, Norman Klopp, L. Adrienne Cupples, Aarno Palotie, Markus Perola, Bamidele O. Tayo, Timo A. Lakka, Matthew Jones, Sarah H. Wild, Patricia B. Munroe, Antti Jula, François Mach, Peter J. Koudstaal, Pirjo Komulainen, Eric Boerwinkle, L. Joost van Pelt, Veikko Salomaa, Ann-Kristin Petersen, Ida Surakka, Andrew Wong, Caroline Hayward, Chi Gao, Cristen J. Willer, Stephen S. Rich, Yi Jen Hung, Peter P. Pramstaller, Diana Kuh, Ron Do, Dominique Arveiler, Mark O. Goodarzi, Ross M. Fraser, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Mary Susan Burnett, Patrik K. E. Magnusson, John C. Chambers, Benjamin M. Neale, Peter Schwarz, Jennifer L. Bolton, Murielle Bochud, Heleen M. den Hertog, Christian Gieger, Cristina Pomilla, Teresa Ferreira, Lars Wallentin, Richa Saxena, André G. Uitterlinden, Kaisa Silander, Ying Wu, Bruce M. Psaty, Jian'an Luan, Hsing-Yi Chang, Jin Chen, Daniel I. Chasman, Ulf Gyllensten, Kari Stefansson, Kauko Heikkilä, Tom Wilsgaard, Alan R. Shuldiner, Carlos Iribarren, Stavroula Kanoni, John Whitfield, Gershim Asiki, Marika Kaakinen, Georg Ehret, Elina Hyppönen, Claudia Langenberg, Gina M. Peloso, Cecilia M. Lindgren, Carlo Sidore, Gudmundur I. Eyjolfsson, Cameron D. Palmer, Jacques S. Beckmann, Hubert Scharnagl, Tanya M. Teslovich, Mary F. Feitosa, Terho Lehtimäki, Steve E. Humphries, Chris Power, Benjamin F. Voight, Stefania Bandinelli, Andrew D. Morris, Gudmar Thorleifsson, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Themistocles L. Assimes, Pascal Bovet, Luigi Ferrucci, Johannes Kettunen, Inês Barroso, Franklyn I. Bennett, Stefan Gustafsson, Paolo Brambilla, Theodore Papamarkou, Elena Tremoli, Janet Seeley, Alex S. F. Doney, Johanna Kuusisto, Giancarlo Cesana, Bruce H. R. Wolffenbuttel, Lars Lind, Stefan R. Bornstein, Åsa Johansson, Anders Hamsten, Marjo-Riitta Järvelin, Krista Fischer, Agneta Siegbahn, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, Do, Ron, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Hyppönen, Elina, Kathiresan, Sekar, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Do, R, Willer, C, Schmidt, E, Sengupta, S, Gao, C, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stančáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Altshuler, D, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Mohlke, K, Ingelsson, E, Abecasis, G, Daly, M, Neale, B, and Kathiresan, S

Subjects
Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Heart disease, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, ISCHEMIC-HEART-DISEASE, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Polymorphism (computer science), Risk Factors, High-density-lipoprotein, Genetic epidemiology, 11 Medical and Health Sciences, Genetics & Heredity, 0303 health sciences, Cholesterol, HDL/blood, Cholesterol levels, Loci, Contribute, Single Nucleotide, LDL/blood, Triglycerides/blood, Cholesterol, Cholesterol, LDL/blood, HDL/blood, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Human, medicine.medical_specialty, TYPE-2 DIABETES-MELLITUS, Biology, Polymorphism, Single Nucleotide, Article, HIGH-DENSITY-LIPOPROTEIN ISCHEMIC-HEART-DISEASE TYPE-2 DIABETES-MELLITUS MENDELIAN RANDOMIZATION CARDIOVASCULAR-DISEASE GENETIC EPIDEMIOLOGY CHOLESTEROL LEVELS LOCI CONTRIBUTE THERAPY, 03 medical and health sciences, Coronary Artery Disease/blood, SDG 3 - Good Health and Well-being, Cardiovascular-disease, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Polymorphism, plasma, Triglycerides, 030304 developmental biology, Science & Technology, Risk Factor, Cholesterol, HDL, Biological Transport, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, Heart-disease, lipoproteins, Endocrinology, chemistry, Therapy, Developmental Biology
Abstract

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.

Published
2013

13. Genome-Wide Association Study Pinpoints a New Functional Apolipoprotein B Variant Influencing Oxidized Low-Density Lipoprotein Levels But Not Cardiovascular Events: AtheroRemo Consortium

Author

Bernhard O. Boehm, Jorma S. A. Viikari, B Thorand, Ilkka Seppälä, Markus Juonala, Winfried März, Tanja B. Grammer, Mahir Karakas, Jari Laurikka, Wolfgang Koenig, Norman Klopp, Jari Viik, Antti Jula, Marcus E. Kleber, Nina Hutri-Kähönen, Thomas Illig, Johannes Kettunen, Pekka J. Karhunen, Jussi Hernesniemi, Tuomo Nieminen, Hubert Scharnagl, Mika Kähönen, Terho Lehtimäki, Pekka Kuukasjärvi, Markku Ahotupa, Kari-Matti Mäkelä, Bernhard R. Winkelmann, Matti Tarkka, Jens Baumert, Olli T. Raitakari, Niku Oksala, Reijo Laaksonen, Leo-Pekka Lyytikäinen, Kjell Nikus, and Tomi Laitinen

Subjects
Male, Atherosclerosis, Coronary Artery Disease, Genome-wide Association Study, Lipoproteins, Oxidative Stress, Apolipoprotein B, Population, Oxidized low density lipoprotein, Mutation, Missense, Genome-wide association study, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Genotype, Genetics, Humans, Genetic Predisposition to Disease, education, Genetics (clinical), 030304 developmental biology, Aged, Apolipoproteins B, Aged, 80 and over, 0303 health sciences, education.field_of_study, biology, Genetic Variation, ta3121, Middle Aged, 3. Good health, Lipoproteins, LDL, Cardiovascular Diseases, biology.protein, Female, Cardiology and Cardiovascular Medicine, Lipoprotein, Genome-Wide Association Study
Abstract

Background— Oxidized low-density lipoprotein may be a key factor in the development of atherosclerosis. We performed a genome-wide association study on oxidized low-density lipoprotein and tested the impact of associated single-nucleotide polymorphisms (SNPs) on the risk factors of atherosclerosis and cardiovascular events. Methods and Results— A discovery genome-wide association study was performed on a population of young healthy white individuals (N=2080), and the SNPs associated with a P –8 were replicated in 2 independent samples (A: N=2912; B: N=1326). Associations with cardiovascular endpoints were also assessed with 2 additional clinical cohorts (C: N=1118; and D: N=808). We found 328 SNPs associated with oxidized low-density lipoprotein. The genetic variant rs676210 (Pro2739Leu) in apolipoprotein B was the proxy SNP behind all associations ( P =4.3×10 –136 , effect size=13.2 U/L per allele). This association was replicated in the 2 independent samples (A and B, P =2.5×10 –47 and 1.1×10 –11 , effect sizes=10.3 U/L and 7.8 U/L, respectively). In the meta-analyses of cohorts A, C, and D (excluding cohort B without angiographic data), the top SNP did not associate significantly with the age of onset of angiographically verified coronary artery disease (hazard ratio=1.00 [0.94–1.06] per allele), 3-vessel coronary artery disease (hazard ratio=1.03 [0.94–1.13]), or myocardial infarction (hazard ratio=1.04 [0.96–1.12]). Conclusions— This novel genetic marker is an important factor regulating oxidized low-density lipoprotein levels but not a major genetic factor for the studied cardiovascular endpoints.

Published
2013
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14. Discovery and refinement of loci associated with lipid levels

Author

Benjamin F. Voight, Stefania Bandinelli, Pascal Bovet, Latonya F. Been, Ci Song, Luigi Ferrucci, Johannes Kettunen, Andrew D. Morris, Mary Susan Burnett, Ronald M. Krauss, Igor Rudan, Heleen M. den Hertog, Stavroula Kanoni, G. Kees Hovingh, Elina Hyppönen, Kauko Heikkilä, Richard S. Cooper, Daniel I. Chasman, Bruna Gigante, Stefan Gustafsson, Jian'an Luan, Sarah H. Wild, Patricia B. Munroe, Göran Hallmans, Jeffrey R. O'Connell, Danish Saleheen, Aarno Palotie, Leena Moilanen, Jerome I. Rotter, Caroline Hayward, Jennifer L. Bragg-Gresham, Nicholas G. Martin, Claudia Langenberg, George Dedoussis, Carlo Sidore, Ulf Gyllensten, Marika Kaakinen, Jing Hua Zhao, Aimo Ruokonen, Diana Kuh, Maria Dimitriou, Shih-Yi Lin, Gina M. Peloso, Marcus E. Kleber, Christopher J. Groves, Alena Stančáková, Michel Burnier, Patrik K. E. Magnusson, John C. Chambers, Giancarlo Cesana, Francis S. Collins, Gabrielle Müller, Angela Döring, Colin A. McKenzie, Paul Elliott, Lars Lind, Vilmundur Gudnason, Dharambir K. Sanghera, Jean Ferrières, Toshiko Tanaka, Stefan R. Bornstein, Gershim Asiki, Jacques S. Beckmann, Anneli Pouta, Timo A. Lakka, Daniel J. Rader, Elizabeth H. Young, Kelly A. Volcik, Dena G. Hernandez, Ann-Kristin Petersen, Kristian Hveem, Amy J. Swift, Murielle Bochud, Pierre Meneton, Paul M. Ridker, Kathleen Stirrups, Stephen S. Rich, Isleifur Olafsson, Ruth J. F. Loos, Serena Sanna, Markus Perola, Meena Kumari, Cameron D. Palmer, Carlos Iribarren, Nancy L. Pedersen, Mark O. Goodarzi, Panos Deloukas, Norman Klopp, Cristina Pomilla, Stephen E. Epstein, Antti Jula, Themistocles L. Assimes, Martina Müller-Nurasyid, Marjo-Riitta Järvelin, Chao A. Hsiung, Sonia Shah, Christian Gieger, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Nicholas J. Wareham, Krista Fischer, Wendy L. McArdle, Linda S. Adair, Kay-Tee Khaw, Bruce M. Psaty, André G. Uitterlinden, Aaron Isaacs, Tõnu Esko, Jennifer L. Bolton, Rebecca N. Nsubuga, Eric Boerwinkle, L. Joost van Pelt, Jouko Saramies, François Mach, Pierre Fontanillas, Teresa Ferreira, Lars Wallentin, Michael Boehnke, Christa Meisinger, Wayne Huey-Herng Sheu, Gonçalo R. Abecasis, Inês Barroso, Franklyn I. Bennett, Dmitry Shungin, Jaakko Kaprio, Kirsten Ohm Kyvik, Deepti Gurdasani, Anne U. Jackson, Paolo Brambilla, Georg Ehret, Cecilia M. Lindgren, Fernando Rivadeneira, Theodore Papamarkou, Jaakko Tuomilehto, Cristen J. Willer, Martin L. Buchkovich, Antero Kesäniemi, Hubert Scharnagl, Xiaohui Li, Elena Tremoli, Nelson B. Freimer, Mika Kähönen, Ron Do, Karen L. Mohlke, Thomas Illig, Gudmar Thorleifsson, Peter J. Koudstaal, Andres Metspalu, Ulf de Faire, Dominique Arveiler, Harald Grallert, Jaana Lindström, Laurence Tiret, Jaspal S. Kooner, Braxton D. Mitchell, Sebanti Sengupta, Gonneke Willemsen, Anna-Liisa Hartikainen, Terho Lehtimäki, Steve E. Humphries, Peter Schwarz, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Tom Wilsgaard, Janet Seeley, Alex S. F. Doney, Alan R. Shuldiner, John Whitfield, Markku Laakso, Peter Vollenweider, Gudmundur I. Eyjolfsson, Winfried März, Mika Kivimäki, Ying Wu, Johanna Kuusisto, Andrew A. Hicks, Bruce H. R. Wolffenbuttel, May E. Montasser, Bamidele O. Tayo, Unnur Thorsteinsdottir, Muredach P. Reilly, Leo-Pekka Lyytikäinen, Eric Kim, John Danesh, Ida Surakka, Åsa Johansson, Anders Hamsten, Thomas Quertermous, Hsing-Yi Chang, Jin Chen, Agneta Siegbahn, Narisu Narisu, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, Sekar Kathiresan, Manjinder S. Sandhu, Leif Groop, Jose M. Ordovas, Alan B. Feranil, Evelin Mihailov, Hilma Holm, Pontiano Kaleebu, Lindsay L. Waite, Ramaiah Nagaraja, Andrew Wong, Rona J. Strawbridge, David P. Strachan, Yii-Der Ida Chen, Tamara B. Harris, Jackie F. Price, Aravinda Chakravarti, Veikko Salomaa, Sailaja Vedantam, Albert Hofman, Devin Absher, Ross M. Fraser, Kaisa Silander, Pirjo Komulainen, Yi Jen Hung, Peter P. Pramstaller, Kari Stefansson, Aroon D. Hingorani, Tanya M. Teslovich, Matti Uusitupa, L. Adrienne Cupples, Cisca Wijmenga, Lori L. Bonnycastle, Ilja M. Nolte, Andrea Ganna, Ken K. Ong, Inger Njølstad, Bernhard O. Boehm, Nicholas W.J. Wainwright, Richa Saxena, Rainer Rauramaa, Louise A. Donnelly, James F. Wilson, Matthew Jones, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Massimo Mangino, John J.P. Kastelein, Martha L. Gravito, Mark I. McCarthy, Evita G. Van Den Herik, Joel N. Hirschhorn, Nilesh J. Samani, Daniel F. Freitag, Ayse Demirkan, Mary F. Feitosa, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Chris Power, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Willer, C, Schmidt, E, Sengupta, S, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Do, R, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stancáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Kathiresan, S, Mohlke, K, Ingelsson, E, Abecasis, G, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Ehret, Georg Benedikt, Mach, François, Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, National Institute for Health Research, Global Lipids Genetics Consortium, Willer, Cristen, Sengupta, Sebanti, Peloso, Gina, Hypponen, Elina Tuulikki, and Abecasis, Gonçalo R

Subjects
Netherlands Twin Register (NTR), HOMEOSTASIS, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Blood lipids, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, European Continental Ancestry Group/genetics, triglycerides, IDENTIFIES 13, 11 Medical and Health Sciences, African Continental Ancestry Group, 2. Zero hunger, Genetics, Genetics & Heredity, ddc:616, RISK, 0303 health sciences, Cholesterol, HDL/blood, PLASMA, Global Lipids Genetics Consortium, Cholesterol, HDL/blood/genetics, Lipid, Lipids, 3. Good health, LDL/blood, Triglycerides/blood, Lipids/blood/genetics, Cholesterol, Cholesterol, LDL/blood, DENSITY-LIPOPROTEIN CHOLESTEROL, CARDIOVASCULAR-DISEASE, HDL/blood, CORONARY-ARTERY-DISEASE, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, coronary artery disease, TRAITS, Human, Coronary Artery Disease/blood/genetics, Asian Continental Ancestry Group, Genotype, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Black People, HEART-DISEASE, Biology, Article, White People, lipids, 03 medical and health sciences, Coronary Artery Disease/blood, CORONARY-ARTERY-DISEASE DENSITY-LIPOPROTEIN CHOLESTEROL GENOME-WIDE ASSOCIATION HEART-DISEASE CARDIOVASCULAR-DISEASE SUSCEPTIBILITY LOCI IDENTIFIES 13 RISK GENE METAANALYSIS, Triglycerides/blood/genetics, Asian People, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Asian Continental Ancestry Group/genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genotyping, Triglycerides, METAANALYSIS, 030304 developmental biology, Science & Technology, Lipids/blood, Cholesterol, HDL, cholesterol, African Continental Ancestry Group/genetics, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, GENE, chemistry, Cholesterol, LDL/blood/genetics, Lipoprotein, Developmental Biology, Genome-Wide Association Study
Abstract

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10 -8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. © 2013 Nature America, Inc. All rights reserved.

Published
2013
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15. A comparison of the accuracy of Illumina HumanHT-12 v3 Expression BeadChip and TaqMan qRT-PCR gene expression results in patient samples from the Tampere Vascular Study

Author

Ilkka Seppälä, Mari Levula, Mika Kähönen, Niku Oksala, Norman Klopp, Leo-Pekka Lyytikäinen, Thomas Illig, Emma Raitoharju, Reijo Laaksonen, and Terho Lehtimäki

Subjects
0303 health sciences, Gene Expression, Reproducibility of Results, 030204 cardiovascular system & hematology, Biology, Molecular biology, Polymerase Chain Reaction, Sensitivity and Specificity, Plaque, Atherosclerotic, 03 medical and health sciences, 0302 clinical medicine, Real-time polymerase chain reaction, Gene expression, TaqMan, Humans, In patient, Cardiology and Cardiovascular Medicine, 030304 developmental biology, Genome-Wide Association Study
Abstract

Aims This study was set up to compare the accuracy, sensitivity and specificity of gene expression results between the Illumina HumanHT-12 v3 Expression BeadChip (GWE) and the TaqMan qRT-PCR low-density array (LDA) in atherosclerotic plaques. Methods Gene expression levels of 196 genes were determined from 22 atherosclerotic samples and 6 controls with both the GWE and the LDA. Results The accuracies of GWE in comparison to that of qRT-PCR for absolute fold changes (FC) 1.2, 1.6, 2.0 and 3.0 between cases and controls were 73.5%, 79.1%, 72.4% and 60.7%, respectively. The correlation of expression measurements between these methods was good ( r = 0.87, y = 0.151 + 0.586 x ), and the Bland–Altman plot showed that for highly up- or down-regulated transcripts, GWE yields lower absolute FC values than LDA. Conclusion Gene expression results obtained with the GWE are replicated with high accuracy in LDA, even for technically demanding atherosclerotic samples.

Published
2013
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16. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences

Subjects
Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2016

17. Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations

Author

Gertrud Eckstein, John M. C. Connell, Peter Lichtner, Susana Eyheramendy, Thomas Meitinger, Angela Döring, Nilesh J. Samani, Piret Kelgo, Morris J. Brown, Martin Farrall, Peeter Juhanson, Norman Klopp, Christian Gieger, Thomas Illig, Kärt Tomberg, Philip Howard, Elin Org, Bright, Stephen Newhouse, Abiodun Onipinla, Anna F. Dominiczak, Margus Viigimaa, Maris Laan, Sue Shaw-Hawkins, Patricia B. Munroe, Siim Sõber, Gudrun Veldre, Mark J. Caulfield, Tiina Rebane, Richard Dobson, and H.-Erich Wichmann

Subjects
Adult, Adolescent, Population, Blood Pressure, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Essential hypertension, Polymorphism, Single Nucleotide, White People, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Molecular Biology, Gene, Genetics (clinical), Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, education.field_of_study, Association Studies Articles, General Medicine, Middle Aged, Cadherins, medicine.disease, 3. Good health, Minor allele frequency, Blood pressure, Hypertension, Genome-Wide Association Study
Abstract

Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395 912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10(-5), effect -1.40 mmHg; SBP, P = 0.007, effect -1.56 mmHg; HYP, P = 5.30 x 10(-8), OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.

Published
2016

18. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. 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S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., 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Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., 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Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016

19. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author

Timo A. Lakka, Kathleen Stirrups, Jean Ferrières, Ying Wu, Gulum Kosova, Toby Johnson, Heather M. Stringham, Bruce M. Psaty, Bruna Gigante, Göran Hallmans, Cornelia M. van Duijn, Kae Woei Liang, Niclas Eriksson, N. William Rayner, Lynda M. Rose, Stavroula Kanoni, Xueling Sim, Evangelos Evangelou, Philippe Froguel, Michel Burnier, Andrew P. Morris, Olle Melander, Martin Farrall, Albert V. Smith, Brendan J. Keating, Thomas Illig, Johan Sundström, Dorret I. Boomsma, Kate Witkowska, Ellen M. Schmidt, Aki S. Havulinna, Ann-Kristin Petersen, Paul F. O'Reilly, Young Jin Kim, Kari Kuulasmaa, Tom Wilsgaard, John D. Eicher, Marcus E. Kleber, Francis S. Collins, Rona J. Strawbridge, Ronald M. Krauss, Fotios Drenos, Stuart K. Kim, Ken K. Ong, Pascal Bovet, Danish Saleheen, Jaspal S. Kooner, Karl-Heinz Herzig, Tien Yin Wong, Benjamin F. Voight, Stefania Bandinelli, Stéphane Lobbens, Colin A. McKenzie, Jing Hua Zhao, Terrence Forrester, Louise A. Donnelly, Alice Stanton, Jean Dallongeville, Kirill V. Tarasov, Narisu Narisu, Jürgen Gräßler, Luigi Ferrucci, Peter S. Sever, Paul Elliott, Tune H. Pers, Andrew J. Smith, Tomas Axelsson, Young Ah Shin, Nora Franceschini, James F. Wilson, Vilmundur Gudnason, Kati Kristiansson, Andrew A. Hicks, Kent D. Taylor, Genovefa Kolovou, Andrew D. Morris, André G. Uitterlinden, Serena Sanna, Xiuqing Guo, Honghuang Lin, Aravinda Chakravarti, Wayne Huey-Herng Sheu, Panos Deloukas, Linda S. Adair, Diana Kuh, Murielle Bochud, Eric Boerwinkle, Inger Njølstad, Meena Kumari, Norman Klopp, Leo-Pekka Lyytikäinen, Steven C. Hunt, Weihua Zhang, Tõnu Esko, Pierre Meneton, Markus Perola, Erik P A Van Iperen, Georg Ehret, Veikko Salomaa, Lars Lind, Zoltán Kutalik, Cristiano Fava, Caroline Hayward, Hugh S. Markus, Teresa Ferreira, Stefan R. Bornstein, Vasyl Pihur, Patricia B. Munroe, Anne U. Jackson, Eirini Marouli, Gabriele Müller, Damiano Baldassarre, Jacques E. Rossouw, Dan E. Arking, Maija Hassinen, Nicholas J. Wareham, Robert Roberts, Daniel I. Chasman, I. Shou Chang, Sylvain Sebert, Tove Fall, Roby Joehanes, Patrik K. E. Magnusson, John C. Chambers, Peter Vollenweider, Wen Jane Lee, Dmitry Shungin, Mathias Gorski, Christopher Newton-Cheh, Anders Franco-Cereceda, Ching-Yu Cheng, Yun Kyoung Kim, Ruth J. F. Loos, Lude Franke, Karen L. Mohlke, Yii-Der Ida Chen, Carlos Iribarren, Martina Müller-Nurasyid, Alexander Teumer, Andrew D. Johnson, Antonella Mulas, Ulf Gyllensten, Martin D. Tobin, George Dedoussis, Rainford J. Wilks, Joshua C. Bis, Beverley Balkau, Jie Yao, Frida Renström, Themistocles L. Assimes, Morris Brown, Inês Barroso, Hyun Min Kang, Loic Yengo, Mika Kähönen, Christopher J. Groves, Kirsti Kvaløy, Rainer Rauramaa, Heribert Schunkert, Satu Männistö, Marjo-Riitta Järvelin, Nancy L. Pedersen, Karl Gertow, Rick Jansen, Thomas Quertermous, Jarmo Virtamo, Lazaros Lataniotis, Serge Hercberg, Paul M. Ridker, Osorio Meirelles, Jostein Holmen, Phil Howard, G. Kees Hovingh, Jeanette Erdmann, Jong-Young Lee, Peter Schwarz, Ramaiah Nagaraja, Elizabeth Theusch, Wei Zhao, Sonia Shah, Chao A. Hsiung, Santhi K. Ganesh, Richard S. Cooper, John M. C. Connell, Jian'an Luan, Graciela E. Delgado, Eric Kim, Daniel Levy, Li Lin, Jerome I. Rotter, Andres Metspalu, Nabila Bouatia-Naji, Christopher J. O'Donnell, Roberto Elosua, Andrew Wong, Alanna C. Morrison, Juha Saltevo, Michael R. Barnes, Alan B. Weder, Kay-Tee Khaw, Leena Moilanen, Peter S. Chines, Claudia Langenberg, Marika Kaakinen, Asif Rasheed, Annette Peters, Angela Döring, Alena Stančáková, Richard A. Jensen, Jaana Lindström, Alison H. Goodall, Toshiko Tanaka, Loukianos S. Rallidis, Dabeeru C. Rao, Ann-Christine Syvänen, Alun Evans, Brenda W.J.H. Penninx, Sarah Edkins, Xiaohui Li, Neil Poulter, Jouko Saramies, Ulf de Faire, Walter Palmas, Jaakko Tuomilehto, Louise V. Wain, Cristina Menni, Stephen Bevan, Maria X. Sosa, Nanette R. Lee, Anuj Goel, Germaine C. Verwoert, Kjell Nikus, Helen R. Warren, May E. Montasser, Ren-Hua Chung, Francesco Gianfagna, Kristian Hveem, Rainer Rettig, Unnur Thorsteinsdottir, Lori L. Bonnycastle, Tim D. Spector, Paul W. Franks, Bamidele O. Tayo, Ilja M. Nolte, John Danesh, E. Shyong Tai, Mika Kivimäki, Devin Absher, Oddgeir L. Holmen, Per Eriksson, Pirjo Komulainen, Peter P. Pramstaller, Cameron D. Palmer, He Gao, Elena Tremoli, H.-Erich Wichmann, Myriam Fornage, Gyda Bjornsdottir, Afshin Parsa, Anders Hamsten, Terho Lehtimäki, Lasse Folkersen, Janine F. Felix, Anna F. Dominiczak, Hinco J. Gierman, Edward G. Lakatta, Alex S. F. Doney, Erik Ingelsson, Colin N. A. Palmer, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Vladan Mijatovic, Mark I. McCarthy, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Stefan Enroth, Mark J. Caulfield, Gudmar Thorleifsson, Tsun-Po Yang, François Mach, Cristen J. Willer, Claudia P. Cabrera, Aline Wagner, Michael Boehnke, Elias Salfati, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Harm-Jan Westra, Harold Snieder, Mark O. Goodarzi, M. Arfan Ikram, Fred Paccaud, Johannes H. Smit, Anna-Liisa Hartikainen, Xiaofeng Zhu, Markku Laakso, Ahmad Vaez, Albert Hofman, Amy J. Swift, Maria Hughes, I. Te Lee, Aroon D. Hingorani, Matti Uusitupa, Oscar H. Franco, Kenneth Rice, Veronique Vitart, Ross M. Fraser, Jouke-Jan Hottenga, Kari Stefansson, Dhananjay Vaidya, Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Saw Swee Hock School of Public Health, National University of Singapore (NUS), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Michigan System, Department of Computational Medicine and Bioinformatics (DCM&B), Queen Mary University of London (QMUL), GlaxoSmithKline, Glaxo Smith Kline, deCODE genetics [Reykjavik], University of Cambridge [UK] (CAM), University of Dundee, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Karolinska University Hospital [Stockholm], Umea University Hospital, Lund University [Lund], Queen's University [Belfast] (QUB), National Institutes of Health, Department of Genomics of Common Disease, Imperial College London, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), National Institute of Health and Welfare, Institute for Molecular Medicine Finland (FIMM), University College London Hospitals (UCLH), University Hospital of Heidelberg, Harbor UCLA Medical Center [Torrance, Ca.], University of Tampere, University of Verona (UNIVR), Uppsala University Hospital, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Stanford University School of Medicine [CA, USA], Medical School University of Athens, Partenaires INRAE, Children's Hospital Oakland Research Institute, Boston Children's Hospital, Broad Institute of Harvard and MIT, University of Copenhagen = Københavns Universitet (KU), Statens Serum Institut [Copenhagen], Framingham Heart Dis Epidemiol Study, Department of Psychiatry, VU University Medical Center [Amsterdam], National Heart, Lung and Blood Institute, Osong Health Technology Administration Complex, University of Pennsylvania, Department of Genetics, University of North Carolina at Chapel Hill (UNC), Loyola University [Chicago], Centre Hospitalier Universitaire Vaudois (CHUV), Hudson Alpha Institute for Biotechnology, Erasmus University Rotterdam, Department of Medical Sciences, Uppsala University, Università degli Studi di Milano [Milano] (UNIMI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], University of Lincoln, University of Washington [Seattle], Amgen Inc., The University of Texas Health Science Center at Houston (UTHealth), VU University Amsterdam, University of Dresden Medical School, Université de Lausanne (UNIL), Healthcare NHS Trust, National Health Research Institutes, National University Health System [Singapore] (NUHS), Duke-NUS Medical School [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National Human Genome Research Institute (NHGRI), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Radiology and nuclear medicine, EMGO - Mental health, Lin, Li, Mach, François, ProdInra, Migration, University of Oxford, Università degli studi di Verona = University of Verona (UNIVR), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Vrije Universiteit Amsterdam [Amsterdam] (VU), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO+ - Lifestyle, Overweight and Diabetes, Biological Psychology, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Danesh, John [0000-0003-1158-6791], Khaw, Kay-Tee [0000-0002-8802-2903], Markus, Hugh [0000-0002-9794-5996], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Medical Microbiology & Infectious Diseases, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Clinical Genetics, Biochemistry, National Institute for Health Research, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), CHROMATIN, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Blood Pressure, SUSCEPTIBILITY, Bioinformatics, Cardiovascular, Genome-wide association studies, Medical and Health Sciences, single nucleotide polymorphism, CHARGE-EchoGen consortium, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, African Continental Ancestry Group, Genetics & Heredity, Genetics, ddc:616, Kidney, Framingham Risk Score, Cultured, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, African Continental Ancestry Group/genetics, Asian Continental Ancestry Group/genetics, Blood Pressure/genetics, Genome-Wide Association Study, Humans, Hypertension/genetics, Hypertension/pathology, Microarray Analysis, Polymorphism, Single Nucleotide, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypertension/genetics/pathology, Hypertension, Medical genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, TRAITS, Biotechnology, Asian Continental Ancestry Group, medicine.medical_specialty, CHARGE-EchoGen Consortium, Cells, Black People, BIOLOGY, Single-nucleotide polymorphism, Biology, Blood pressure, hypertension, genetics, single nucleotide polymorphism, GWAS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, CELL-TYPES, METAANALYSIS, Genetic association, Science & Technology, CHARGE-HF consortium, 06 Biological Sciences, Genetic architecture, 030104 developmental biology, Blood pressure, CHARGE-HF Consortium, ARTERIAL-HYPERTENSION, Developmental Biology
Abstract

To dissect the genetic architecture of blood pressure (BP) and assess how its elevation promotes downstream cardiovascular diseases, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry. Genotypes from an additional 140,886 individuals of European ancestry were used as validation for loci reaching genome-wide significance but without prior support in the literature. We identified 66 BP loci, of which 17 were novel and 15 harbored multiple distinct association signals, and which together explain up to 3.5% of BP variation. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in BP control through modulating blood vessel tone and fluid filtration across multiple tissues, not solely the kidney. Importantly, the 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent (South-Asian, East-Asian and African), confirming that these are ancestral physiological effects that arose prior to human migration out of Africa. The 66-SNP BP risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our data expand current knowledge of BP pathways, and also, highlight that BP regulation and its effects may occur in multiple organs and tissues beyond the classic renal system.

Published
2016

20. PSEA: Phenotype Set Enrichment Analysis-A New Method for Analysis of Multiple Phenotypes

Author

Karsten Suhre, Annette Peters, H-Erich Wichmann, Norman Klopp, Konrad Oexle, Thomas Meitinger, Angela Döring, Janina S. Ried, Christian Gieger, Christa Meisinger, and Juliane Winkelmann

Subjects
Genetics, 0303 health sciences, education.field_of_study, Epidemiology, 030305 genetics & heredity, Population, Univariate, Genome-wide association study, Biology, Phenotype, 03 medical and health sciences, Pleiotropy, Genotype, Identification (biology), education, Genetics (clinical), 030304 developmental biology, Genetic association
Abstract

Most genome-wide association studies (GWAS) are restricted to one phenotype, even if multiple related or unrelated phenotypes are available. However, an integrated analysis of multiple phenotypes can provide insight into their shared genetic basis and may improve the power of association studies. We present a new method, called "phenotype set enrichment analysis" (PSEA), which uses ideas of gene set enrichment analysis for the investigation of phenotype sets. PSEA combines statistics of univariate phenotype analyses and tests by permutation. It does not only allow analyzing predefined phenotype sets, but also to identify new phenotype sets. Apart from the application to situations where phenotypes and genotypes are available for each person, the method was adjusted to the analysis of GWAS summary statistics. PSEA was applied to data from the population-based cohort KORA F4 (N = 1,814) using iron-related and blood count traits. By confirming associations previously found in large meta-analyses on these traits, PSEA was shown to be a reliable tool. Many of these associations were not detectable by GWAS on single phenotypes in KORA F4. Therefore, the results suggest that PSEA can be more powerful than a single phenotype GWAS for the identification of association with multiple phenotypes. PSEA is a valuable method for analysis of multiple phenotypes, which can help to understand phenotype networks. Its flexible design enables both the use of prior knowledge and the generation of new knowledge on connection of multiple phenotypes. A software program for PSEA based on GWAS results is available upon request.

Published
2012

21. Large-scale association analysis identifies new risk loci for coronary artery disease

Author

Benjamin F. Voight, Andrew D. Morris, G. Kees Hovingh, Anthony J. Balmforth, Hanneke Basart, Alistair S. Hall, Dominique Gauguier, Bok Ghee Han, Martina Müller-Nurasyid, Sarah Parish, Jarmo Virtamo, Christa Meisinger, Peter Wagner, George Dedoussis, Philipp S. Wild, Kari Stefansson, Jean-Baptiste Cazier, Kathleen Stirrups, Jiyoung Lee, Adrienne Cupples, Stavroula Kanoni, Danish Saleheen, Christian Hengstenberg, Svati H. Shah, Panos Deloukas, Anuj Goel, Stefan Blankenberg, Sian Tsung Tan, Alison H. Goodall, Tõnu Esko, Eric Boerwinkle, Gudmundur Thorgeirsson, Peter S. Braund, Joshua W. Knowles, Olle Melander, C. Ellen van der Schoot, Silke Rosinger, Maria Dimitriou, Wolfgang Koenig, Michael Boehnke, François Cambien, Per Lundmark, Dmitry Shungin, Wolfgang Kratzer, Pierre Zalloua, Reijo Laaksonen, Jean Ferrières, Villi Gudnason, Thorsten Kessler, Daniel J. Rader, Niclas Eriksson, Dominique Arveiler, Natalie R. van Zuydam, Kari Kuulasmaa, N. William Rayner, Sarah E. Hunt, Gudmar Thorleifsson, Jeanette Erdmann, Samuli Ripatti, Tsun-Po Yang, George A. Wells, Terho Lehtimäki, Kjell Nikus, Pierre Fontanillas, Jorg Hager, Martin Farrall, Jemma C. Hopewell, Frank Kee, Juha Sinisalo, Christopher J. O'Donnell, Asif Rasheed, Mika Kähönen, Genovefa Kolovou, Seraya Maouche, Suzanne Rafelt, Cordelia Langford, Winfried März, Leo-Pekka Lyytikäinen, Christina Willenborg, Weihua Zhang, Kati Kristiansson, Hyo-Soo Kim, Weang K. Ho, Jeong E. Park, Mohan U. Sivananthan, Moritz P. Rumpf, Markku Laakso, Klaus Stark, Philippe Amouyel, Paul W. Franks, Andres Metspalu, Anders Franco-Cereceda, Manjinder S. Sandhu, Nour Eddine El Mokhtari, Nicholas J. Wareham, Robert Roberts, Veikko Salomaa, Thomas Illig, Tomi Pastinen, Robert Clarke, Christof Burgdorf, Leif Groop, Devin Absher, Yangsoo Jang, Mark I. McCarthy, Bernhard O. Boehm, Per Eriksson, Nilesh J. Samani, Inke R. König, Stefan Schreiber, Karin Leander, Simone Claudi-Boehm, Ci Song, Benjamin A. Goldstein, Stephen E. Epstein, Andreas Ziegler, Stanley L. Hazen, Arne Schäfer, Elin Grundberg, Sekar Kathiresan, John R. Thompson, Unnur Thorsteinsdottir, Muredach P. Reilly, Heribert Schunkert, Rory Collins, Thomas Quertermous, Jong-Young Lee, John Danesh, John C. Chambers, Marco M Ferrario, Carlos Iribarren, Claudia Langenberg, Hilma Holm, Rona J. Strawbridge, Alan S. Go, Cristen J. Willer, Ron Do, Emmi Tikkanen, Abbas Dehghan, Evelin Mihailov, Lindsay L. Waite, Patrick Diemert, Willem H. Ouwehand, Eric E. Schadt, Diana Rubin, David Altshuler, Marcus E. Kleber, Markus Perola, Alexandre F.R. Stewart, Jaspal S. Kooner, Themistocles L. Assimes, Inês Barroso, Bruna Gigante, Göran Hallmans, Marja-Liisa Lokki, Aki S. Havulinna, Anders Hamsten, Agneta Siegbahn, Lasse Folkersen, Erik Ingelsson, Martina E. Zimmermann, Colin N. A. Palmer, Paolo Brambilla, Ann-Christine Syvänen, Alun Evans, Åsa Johansson, John F. Peden, Alex S. F. Doney, Hugh Watkins, Johanna Kuusisto, Anders Lundmark, David G. Cox, Hyun Min Kang, Lars Lind, Krista Fischer, Markku S. Nieminen, Annette Peters, Norman Klopp, Stefan Gustafsson, Lars Wallentin, Nancy L. Pedersen, David-Alexandre Trégouët, Ulf de Faire, Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, B, Stirrups, K, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Willer, C, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, J, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Salomaa, V, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Franks, P, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Boehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Schunkert, H, Samani, N, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine

Subjects
Adult, Asian Continental Ancestry Group, Male, Candidate gene, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Population, European Continental Ancestry Group, Quantitative Trait Loci, CAD, Genome-wide association study, Single-nucleotide polymorphism, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Bioinformatics, Polymorphism, Single Nucleotide, Article, White People, coronary artery disease, risk loci, Cell Line, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Risk Factors, medicine, Humans, genetics, Gene Regulatory Networks, Genetic Predisposition to Disease, cardiovascular diseases, Polymorphism, education, 030304 developmental biology, Genetic association, Aged, Genetics, 0303 health sciences, education.field_of_study, Adult, Aged, Asian Continental Ancestry Group, Cell Line, Coronary Artery Disease, genetics, European Continental Ancestry Group, genetics, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Single Nucleotide, Middle Aged, medicine.disease, 3. Good health, Female, Genome-Wide Association Study
Abstract

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r 2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. © 2013 Nature America, Inc. All rights reserved.

Published
2012
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22. Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC)

Author

Norman Klopp, Joseph R. Hibbeln, Susan M. Ring, Sonja Zeilinger, Colin D Steer, Berthold Koletzko, and Eva Lattka

Subjects
Fatty Acid Desaturases, Male, medicine.medical_specialty, 030309 nutrition & dietetics, Medicine (miscellaneous), Polymorphism, Single Nucleotide, Umbilical cord, Article, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, Delta-5 Fatty Acid Desaturase, Fetus, Pregnancy, Fatty Acids, Omega-6, Internal medicine, Fatty Acids, Omega-3, medicine, Humans, Longitudinal Studies, Genetic Association Studies, 030304 developmental biology, FADS, Fetal fatty acid supply, Cord blood, Avon Longitudinal Study of Parents and Children (ALSPAC), chemistry.chemical_classification, Genetics, 0303 health sciences, Nutrition and Dietetics, biology, Fatty acid metabolism, Fatty acid, Fetal Blood, medicine.disease, Fatty acid desaturase, medicine.anatomical_structure, Endocrinology, England, chemistry, Multigene Family, Multivariate Analysis, biology.protein, DNA, Intergenic, Female, Algorithms, Polyunsaturated fatty acid
Abstract

Fetal supply with long-chain PUFA (LC-PUFA) during pregnancy is important for brain growth and visual and cognitive development and is provided by materno–fetal placental transfer. We recently showed that maternal fatty acid desaturase (FADS)genotypes modulate the amounts of LC-PUFA in maternal blood. WhetherFADSgenotypes influence the amounts of umbilical cord fatty acids has not been investigated until now. The aim of the present study was to investigate the influence of maternal and childFADSgenotypes on the amounts of LC-PUFA in umbilical cord venous plasma as an indicator of fetal fatty acid supply during pregnancy. A total of eleven cord plasman-6 andn-3 fatty acids were analysed for association with seventeenFADSgene cluster SNP in over 2000 mothers and children from the Avon Longitudinal Study of Parents and Children. In a multivariable analysis, the maternal genotype effect was adjusted for the child genotype and vice versa to estimate which of the two has the stronger influence on cord plasma fatty acids. Both maternal and childFADSgenotypes and haplotypes influenced amounts of cord plasma LC-PUFA and fatty acid ratios. Specifically, most analysed maternal SNP were associated with cord plasma levels of the precursorn-6 PUFA, whereas the child genotypes were mainly associated with more highly desaturatedn-6 LC-PUFA. This first study onFADSgenotypes and cord fatty acids suggests that fetal LC-PUFA status is determined to some extent by fetal fatty acid conversion. Associations of particular haplotypes suggest specific effects of SNP rs498793 and rs968567 on fatty acid metabolism.

Published
2012
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23. Genetic Variations in Polyunsaturated Fatty Acid Metabolism – Implications for Child Health?

Author

Hans Demmelmair, Berthold Koletzko, Eva Lattka, Mario Klingler, Joachim Heinrich, and Norman Klopp

Subjects
Fatty Acid Desaturases, 030309 nutrition & dietetics, FADS1, FADS2, Medicine (miscellaneous), Single-nucleotide polymorphism, Health Promotion, Bioinformatics, 03 medical and health sciences, Child Development, Nutrigenomics, Genetic variation, Humans, Genetic Predisposition to Disease, Precision Medicine, Child, 030304 developmental biology, Genetic association, chemistry.chemical_classification, Genetics, 0303 health sciences, Polymorphism, Genetic, Nutrition and Dietetics, biology, Fatty acid, Dietary Fats, Asthma, 3. Good health, Fatty acid desaturase, chemistry, Fatty Acids, Unsaturated, biology.protein, Cognition Disorders, Polyunsaturated fatty acid
Abstract

Sufficient nutritional supply with polyunsaturated fatty acids (PUFAs) has long been considered as beneficial for child health, especially in regard to neuronal development and allergic diseases. In recent years, genetic association studies showed that in addition to nutritional influences, the genetic background is highly important for PUFA composition in human tissues. Specifically, polymorphisms in the fatty acid desaturase genes or FADS determine the efficiency of how PUFAs are processed endogenously. Recent gene-nutrition interaction studies suggest that these polymorphisms modulate the effect of nutritional fatty acid intake on complex phenotypes such as cognitive outcomes and asthma risk in children. These early results may provide the basis for future well-specified dietary recommendations to achieve optimal health benefit for all children. This article presents results from recent gene-nutrition interaction studies, discusses its implications for child health, and gives an outlook how this association might translate into clinical practice in the future.

Published
2012
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24. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Author

Jens Baumert, Gerjan Navis, Shelly G. Smith, Peter J. Grant, Anders Hamsten, Frances M K Williams, Russell P. Tracy, James B. Meigs, Maria Grazia Franzosi, Angela M. Carter, François Cambien, Wiek H. van Gilst, Kent D. Taylor, Folkert W. Asselbergs, Marcus E. Kleber, Kurt Lohman, Scott M. Williams, Saonli Basu, Martina Müller-Nurasyid, Angela Silveira, Pim van der Harst, Rory Collins, Geoffrey H. Tofler, Lasse Folkersen, Wolfgang Koenig, Christa Meisinger, Christopher J. O'Donnell, Qiong Yang, Aaron R. Folsom, John C. Chambers, Muredach P. Reilly, Norman Klopp, Weihong Tang, Ming-Huei Chen, Mahir Karakas, Bernhard R. Winkelmann, John Danesh, Sekar Kathiresan, Tamara B. Harris, Tim D. Spector, Pierre-Emmanuel Morange, John F. Peden, Danish Saleheen, Jaspal S. Kooner, Ann-Christine Syvänen, David-Alexandre Trégouët, Winfried März, Bernhard O. Boehm, Robert Clarke, Tiphaine Oudot-Mellakh, Nicholas L. Smith, Vinh Truong, Mary Cushman, André G. Uitterlinden, Lewis C. Becker, Joshua C. Bis, Udo Seedorf, Bengt Sennblad, Anders Franco-Cereceda, Yongmei Liu, Elisabeth M. C. Schrijvers, Hugh Watkins, Barbara McKnight, Diane M. Becker, Jingzhong Ding, Nicole Soranzo, Bruce M. Psaty, Anuj Goel, Per Eriksson, Mohammad Arfan Ikram, Annette Peters, So-Youn Shin, Abbas Dehghan, Lisa R. Yanek, Albert Hofman, Jason H. Moore, Hans L. Hillege, Per Lundmark, Jie Huang, Günther Silbernagel, Jemma C. Hopewell, John Öhrvik, Nena Matijevic, Alison H. Goodall, Maria Sabater-Lleal, Josyf C. Mychaleckyj, Rona J. Strawbridge, Andrew D. Johnson, Radiology & Nuclear Medicine, Epidemiology, Neurology, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), and Vascular Ageing Programme (VAP)

Subjects
Candidate gene, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, CIRCADIAN CLOCK, PLASMINOGEN-ACTIVATOR INHIBITOR-1, Biochemistry, TYPE-1 EXPRESSION, Monocytes, Thrombosis and Hemostasis, Cohort Studies, 0302 clinical medicine, Gene Frequency, Genetics, RISK, 0303 health sciences, ARNTL Transcription Factors, GENETIC-VARIATION, Hematology, LIM Domain Proteins, 3. Good health, ARNTL, CORONARY-ARTERY-DISEASE, RNA Interference, Proteasome Endopeptidase Complex, SUSCEPTIBILITY LOCI, Genotype, Immunology, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Cell Line, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Cell Line, Tumor, Plasminogen Activator Inhibitor 1, SNP, Humans, PLASMA-LEVELS, Allele frequency, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Mucin-3, Gene Expression Profiling, Cell Biology, Molecular biology, Gene expression profiling, PPAR gamma, MYOCARDIAL-INFARCTION, Diabetes Mellitus, Type 2, Gene Expression Regulation, TISSUE, ATPases Associated with Diverse Cellular Activities, Genome-Wide Association Study, Transcription Factors
Abstract

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10−10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10−8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

Published
2012
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25. Polymorphisms in MUC1, MUC2, MUC5B and MUC6 genes are not associated with the risk of chronic atrophic gastritis

Author

Melanie N. Weck, Bernd Frank, Norman Klopp, Hermann Brenner, Elke Raum, Thomas Illig, and Heiko Müller

Subjects
Gastritis, Atrophic, Male, Cancer Research, Genotype, Atrophic gastritis, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Risk Factors, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Neoplastic transformation, Mucin-6, Gene, MUC1, Aged, Genetics, Mucin-2, Stomach, Mucin-1, Mucin, Middle Aged, medicine.disease, Mucin-5B, medicine.anatomical_structure, Oncology, Case-Control Studies, Immunology, Female
Abstract

Mucins represent major components of the mucous layer in the stomach, protecting the underlying epithelium from acid, mechanical trauma, proteases and pathogenic bacteria. Previous studies have shown an association of neoplastic transformation in the stomach with aberrant mucin levels, suggesting a potential role of genetic variation in mucin genes in the development of gastric cancer (GC). We assessed the association of genetic variation in candidate single nucleotide polymorphisms (SNPs) in mucin genes with the risk of chronic atrophic gastritis (CAG), a well-established precursor of GC in the German population-based ESTHER study. We genotyped MUC1 T31T, MUC2 L58P, MUC2 V116M, MUC5B E34G, MUC5B R51W, MUC5B rs2014486 (intronic) and MUC6 V619M for 533 serologically defined CAG cases and 1054 age- and sex-matched controls. None of the analysed SNPs was associated with CAG. However, large studies are needed to disclose or exclude potential weak associations of these SNPs with CAG risk.

Published
2012

26. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author

Norman Klopp, Chih-Mei Chen, Erik Melén, Dirkje S. Postma, Klaus Bønnelykke, Gerard H. Koppelman, Ivan Curjuric, Massimo Mangino, Nicholas J. Timpson, Alexandra I. F. Blakemore, Stephen B. Montgomery, Marjo-Riitta Järvelin, Anneli Pouta, Dorret I. Boomsma, Melanie C. Matheson, Albert Hofman, Matthias Wjst, Hans Bisgaard, Natalija Novak, Deborah Jarvis, Grant W. Montgomery, Frank Geller, Beate St Pourcain, Craig E. Pennell, Manuel A. R. Ferreira, Andre Franke, Alexessander Couto Alves, Frank D. Mentch, Vincent W. V. Jaddoe, Marie Standl, Nicole M. Warrington, Jouke-Jan Hottenga, Jessica L. Buxton, Peter N. Le Souëf, Bjarke Feenstra, Peter D. Sly, Bo L. Chawes, Martina Mueller-Nurasyid, Angela Simpson, Philip J. Thompson, Jacob P. Thyssen, Patrick G. Holt, Eskil Kreiner-Møller, David L. Duffy, Thomas Illig, Johan C. de Jongste, Bo Jacobsson, Joachim Heinrich, Mads Melbye, Wenche Nystad, H-Erich Wichmann, Medea Imboden, Wendy L. McArdle, Carla M. T. Tiesler, Susan M. Ring, Jeff Murray, Lavinia Paternoster, Torkil Menné, Marjan Kerkhof, John Henderson, Ronny Myhre, Lyle J. Palmer, George Davey Smith, Eva Albrecht, Pamela A. F. Madden, Marika Kaakinen, Hansjoerg Baurecht, Nicole Probst-Hensch, Cecilia Kim, Cornelia M. van Duijin, Panos Deloukas, Patrick M. A. Sleiman, Christian Gieger, John A. Curtin, Adnan Custovic, Daniel Glass, Cilla Söderhäll, Annika Sääf, Elke Rodriguez, Nicholas G. Martin, Stephan Weidinger, Tim D. Spector, Adaikalavan Ramasamy, John P. Kemp, Heather A. Boyd, Elisabeth Thiering, David P. Strachan, Anna-Liisa Hartikainen, Hakon Hakonarson, Allan Linneberg, Ralf J. P. van der Valk, Pirro G. Hysi, David M. Evans, Rain Jögi, Ellen A. Nohr, Liesbeth Duijts, Katharina Heim, Veronique Bataille, Fernando Rivadeneira, Maria M. Groen-Blokhuis, Andrew C. Heath, David Ellinghaus, Michael E. March, Holger Prokisch, Regina Foelster-Holst, André G. Uitterlinden, Emmanouil T. Dermitzakis, Juha Pekkanen, Henriette A. Smit, Medical Research Council (MRC), Dermitzakis, Emmanouil, Montgomery, Stephen, Biological Psychology, EMGO+ - Mental Health, Pediatrics, Surgery, Internal Medicine, Epidemiology, Erasmus MC other, Public Health, Groningen Research Institute of Pharmacy, Faculteit Medische Wetenschappen/UMCG, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Male, Genetics of Overweight Young Adults (GOYA) Consortium, Netherlands Twin Register (NTR), Epidemiology, Cell Differentiation/genetics Chromosomes, Human, Pair 11/genetics Chromosomes, Human, Pair 20/genetics Chromosomes, Human, Pair 5 Cytokines/genetics DNA-Binding Proteins/genetics Dermatitis, Atopic/*genetics/immunology Epidermis/immunology Female *Genetic Loci Genetic Predisposition to Disease *Genome-Wide Association Study Humans Intermediate Filament Proteins/genetics Kinesin/genetics Male Polymorphism, Single Nucleotide Risk Transcription Factors/genetics, Chromosomes, Human, Pair 20, Kinesins, Genome-wide association study, Filaggrin Proteins, VARIANTS, Chromosomes, Human, Pair 11/genetics, medicine.disease_cause, Genome-wide association studies, DISEASE, 030207 dermatology & venereal diseases, 0302 clinical medicine, Intermediate Filament Proteins, Epidermis/immunology, ddc:576.5, GENETICS & HEREDITY, Genetics, 0303 health sciences, education.field_of_study, PSORIASIS, Cytokines/genetics, Cell Differentiation, Kinesin, 11 Medical And Health Sciences, Atopic dermatitis, 3. Good health, DNA-Binding Proteins, DIFFERENTIATION, Chromosomes, Human, Pair 5, Cytokines, Female, Dermatitis, Atopic/genetics/immunology, Life Sciences & Biomedicine, Kinesin/genetics, Filaggrin, EXPRESSION, Risk, Cell Differentiation/genetics, Population, Transcription Factors/genetics, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Australian Asthma Genetics Consortium (AAGC), Article, MECHANISMS, Dermatitis, Atopic, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, FILAGGRIN, Humans, SPERMATOGENESIS, Genetic Predisposition to Disease, EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium, education, 030304 developmental biology, Science & Technology, Chromosomes, Human, Pair 11, Odds ratio, 06 Biological Sciences, Immune dysregulation, medicine.disease, Chromosomes, Human, Pair 20/genetics, Genetic Loci, Intermediate Filament Proteins/genetics, Immunology, ASTHMA, Epidermis, CELLULAR MOTILITY, DNA-Binding Proteins/genetics, Genome-Wide Association Study, Transcription Factors, Developmental Biology
Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Published
2012

27. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

Author

Arthur W. Musk, Ernst Omenaas, Dana B. Hancock, Jennie Hui, John W. Holloway, Nora Franceschini, Alan F. Wright, Ma'en Obeidat, Judith M. Vonk, Norman Klopp, Shah Ebrahim, R. Graham Barr, Jerome I. Rotter, Albert Hofman, Jennifer E. Huffman, Kirsi H. Pietiläinen, John Beilby, Bruno H. Ch. Stricker, Xiangjun Gu, Fernando Rivadeneira, James F. Wilson, Fredrik Nyberg, Peter D. Sly, María Soler Artigas, Bonnie R. Joubert, Marjo-Riitta Järvelin, Medea Imboden, Veronique Vitart, Albert V. Smith, Ida Surakka, C.M. Jackson, Susan R. Heckbert, Avan Aihie Sayer, Craig E. Pennell, Matthias Wjst, Ivana Kolcic, Cyrus Cooper, Wei Ang, Ian Sayers, John Britton, George T. O'Connor, Patrick G. Holt, Anna-Liisa Hartikainen, Adaikalavan Ramasamy, Jing Hua Zhao, Jonathan Marchini, Bernd Meibohm, Laura R. Loehr, Mark Eijgelsheim, David Couper, Massimo Mangino, Santosh Dahgam, Vilmundur Gudnason, David P. Strachan, Martin D. Tobin, Rebecca Hardy, Nicole Probst-Hensch, Stephen B. Kritchevsky, George Davey Smith, Tatijana Zemunik, Toby Johnson, Samuli Ripatti, Georg Homuth, Debbie A Lawlor, Thor Aspelund, Henry Völzke, John M. Starr, Aroon D. Hingorani, Khalid A. Al Balushi, Ivan Curjuric, John Henderson, Diana Kuh, Ruth J. F. Loos, Joachim Heinrich, Ozren Polasek, Yongmei Liu, Dirkje S. Postma, Raquel Granell, Akshay Sood, Kari E. North, Beate Koch, Christian Gieger, Tamara B. Harris, Anneli Pouta, David J. Porteous, Daan W. Loth, Sarah H. Wild, Gudny Eiriksdottir, Mladen Boban, Markku Heliövaara, Jonas Brisman, Mika Kähönen, Eva Albrecht, Pirro G. Hysi, Paul Elliott, Stephanie J. London, Guy Brusselle, Myriam Fornage, Thierry Rochat, Kurt Lohman, Ani Manichaikul, David M. Evans, Florian Kronenberg, Caroline Hayward, Harry Campbell, Tricia M. McKeever, So-Youn Shin, Deborah Jarvis, Alanna C. Morrison, Nicole M. Warrington, Holger Schulz, Karen A. Jameson, Stefan Karrasch, Cisca Wijmenga, Richard W Morris, Gauti Kjartan Gislason, Lina Zgaga, Ivica Grković, Alan James, Amanda P. Henry, O. Dale Williams, Jaakko Kaprio, Gemma Cadby, Susan M. Ring, Peter H. Whincup, Thomas Lumley, Nicholas J. Wareham, Lorna M. Lopez, John L. Hankinson, Christopher J Hammond, André G. Uitterlinden, Isabelle Pin, Shona M. Kerr, Alicja R. Rudnicka, Ian J. Deary, Taina Rantanen, Sven Gläser, Wendy L. McArdle, Andrew Wong, Ins Barroso, Lenore J. Launer, S. Goya Wannamethee, Wenbo Tang, Ian P. Hall, Sina A. Gharib, Louise V. Wain, Vesna Boraska, John D Blakey, H.-Erich Wichmann, Anna-Carin Olin, Patricia A. Cassano, H. Marike Boezen, Stipan Janković, Igor Rudan, Andrew D. Morris, Jason Z. Liu, Sarah E. Harris, Clyde Francks, Michael Hunter, Kristin D. Marciante, Stephen S. Rich, Darya Gaysina, Bruce M. Psaty, Melinda C. Aldrich, Melissa E. Garcia, Jemma B. Wilk, Tim D. Spector, Lyle J. Palmer, Guangju Zhai, Epidemiology, Internal Medicine, Public Health, Medical Research Council (MRC), The International Lung Cancer Consortium, Giant consortium, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Oncology, Vital capacity, PROTEIN, Genome-wide association study, BLOOD-PRESSURE, VARIANTS, Pulmonary function testing, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Epidemiology, IMPUTATION, Child, 11 Medical and Health Sciences, POPULATION, Genetics & Heredity, RISK, 0303 health sciences, education.field_of_study, WOMEN, GENETIC-VARIATION, 3. Good health, Respiratory Function Tests, medicine.anatomical_structure, Medical genetics, Life Sciences & Biomedicine, EXPRESSION, medicine.medical_specialty, MECOM, Population, European Continental Ancestry Group, Biology, OBSTRUCTIVE PULMONARY-DISEASE, Article, White People, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, education, METAANALYSIS, POLYMORPHISMS, 030304 developmental biology, Lung, Science & Technology, MORTALITY, GIANT consortium, International Lung Cancer Consortium, 06 Biological Sciences, 030228 respiratory system, Immunology, lung, gene, gwas, Genome-Wide Association Study, Developmental Biology
Abstract

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 x 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Published
2011

28. FADS gene variants modulate the effect of dietary fatty acid intake on allergic diseases in children

Author

Ursula Krämer, C. P. Bauer, Joachim Heinrich, A. von Berg, Stefanie Sausenthaler, Stefan Röder, Eva Lattka, Heinz Erich Wichmann, Dietrich Berdel, Norman Klopp, Olf Herbarth, Beate Schaaf, M. Standl, Sibylle Koletzko, and Berthold Koletzko

Subjects
030309 nutrition & dietetics, FADS1, FADS2, Immunology, Physiology, Single-nucleotide polymorphism, Biology, Atopy, Allergic sensitization, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, 030212 general & internal medicine, Asthma, 2. Zero hunger, chemistry.chemical_classification, 0303 health sciences, business.industry, Fatty acid, Odds ratio, medicine.disease, 3. Good health, Biotechnology, chemistry, business
Abstract

The association between dietary fatty acid intake and the development of atopic diseases has been inconsistent. This could be due to inter-individual genetic differences in fatty acid metabolism.The aim of the current study was to assess the influence of FADS1 FADS2 gene cluster polymorphisms on the association between dietary fatty acid intake and atopic diseases and allergic sensitization in 10-year-old children.The analysis was based on data from two German prospective birth cohort studies. Data on margarine and fatty acid intake were collected using a food frequency questionnaire. Information on atopic diseases was collected using a questionnaire completed by the parents. Specific IgE against common food and inhalant allergens were measured. Six variants of the FADS1 FADS2 gene cluster (rs174545, rs174546, rs174556, rs174561, rs174575 and rs3834458) were tested. Logistic regression modelling, adjusted for gender, age, maternal education level and study centre, was used to analyse the association between fatty acid intake and atopic diseases stratified by genotype.No significant association was found between the six FADS single nucleotide polymorphisms (SNPs) and allergic diseases or atopic sensitization. The total n-3/total n-6 ratio was positive associated with an increased risk of hayfever in homozygous major allele carriers ranging from an adjusted odds ratios of 1.25 (95%-CI: 1.00-1.57) to 1.31 (95%-CI: 1.01-1.69) across the six tested SNPs although this association was not significant anymore after correcting for multiple testing. Daily margarine intake was significantly associated with asthma [1.17 (1.03-1.34) to 1.22 (1.06-1.40)] in individuals carrying the homozygous major allele. This association was also significant after correcting for multiple testing. CONCLUSIONS& CLINICAL RELEVANCE: The association between dietary intake of fatty acids and allergic diseases might be modulated by FADS gene variants in children.

Published
2011

29. A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease

Author

Thomas Foki, Juliane Winkelmann, Tim M. Strom, Klaus Seppi, Walter Pirker, Eva M. Reinthaler, Anna Benet-Pagès, Shaila C. Rossle, Dietrich Haubenberger, Marc N. Offman, Thomas Brücke, Ashot S. Harutyunyan, Claudia Trenkwalder, Fritz Zimprich, Elisabeth Graf, Sebastian H. Eck, Werner Poewe, Stefan Presslauer, Alexander Zimprich, Gerhard Ransmayr, Eva C. Schulte, Robert Kralovics, Peter Lichtner, Annette Peters, Elisabeth Wolf, Eduard Auff, Burkhard Rost, Norman Klopp, Walter Struhal, Brit Mollenhauer, Christoph Hotzy, Thomas Meitinger, Regina Katzenschlager, and Sabine Spielberger

Subjects
Nonsynonymous substitution, Adult, Male, Protein Conformation, Mutation, Missense, Vesicular Transport Proteins, Endosomes, Biology, Cohort Studies, 03 medical and health sciences, VPS35, 0302 clinical medicine, Genome-wide association, Common LRRK2 mutation, Gene, Receptors, Variants, Server, Risk, Report, Genetics, Missense mutation, Humans, Genetics(clinical), Age of Onset, Genetics (clinical), Exome sequencing, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, Haplotype, Genetic Variation, Hydrogen Bonding, Parkinson Disease, Middle Aged, Penetrance, Pedigree, Retromer complex, Haplotypes, Female, Age of onset, 030217 neurology & neurosurgery, trans-Golgi Network
Abstract

To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.

Published
2011
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30. Genetic Variation in the Prostate Stem Cell Antigen Gene and Upper Gastrointestinal Cancer in White Individuals

Author

Harvey A. Risch, Marilie D. Gammon, Bernd Frank, Thomas Illig, Charles S. Rabkin, Melanie N. Weck, Thomas L. Vaughan, Kenneth E.L. McColl, Alan Dawson, Jolanta Lissowska, Heiko Müller, Wong Ho Chow, Georgina L. Hold, Elke Raum, Paul Lochhead, Hermann Brenner, Norman Klopp, Michael T.H. Ng, and Emad M. El–Omar

Subjects
Gastritis, Atrophic, Male, Risk, medicine.medical_specialty, Esophageal Neoplasms, Atrophic gastritis, Population, Adenocarcinoma, GPI-Linked Proteins, Polymorphism, Single Nucleotide, Gastroenterology, White People, Article, Helicobacter Infections, Antigens, Neoplasm, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, education, Stomach cancer, Gastrointestinal Neoplasms, education.field_of_study, Helicobacter pylori, Hepatology, biology, Cancer, Odds ratio, Esophageal cancer, biology.organism_classification, medicine.disease, Neoplasm Proteins, Case-Control Studies, Immunology, Carcinoma, Squamous Cell, Female
Abstract

Background & Aims An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen ( PSCA ) gene has been reported for several Asian populations. We set out to determine whether such an association exists in white individuals. Methods We genotyped 166 relatives of gastric cancer patients, including 43 Helicobacter pylori -infected subjects with hypochlorhydria and gastric atrophy, 65 infected subjects without these abnormalities, 58 H pylori -negative relatives, and 100 population controls. Additionally, a population-based study of chronic atrophic gastritis provided 533 cases and 1054 controls. We then genotyped 2 population-based, case-control studies of upper gastrointestinal cancer: the first included 312 gastric cancer cases and 383 controls; the second included 309 gastric cancer cases, 159 esophageal cancer cases, and 211 controls. Odds ratios were computed from logistic models and adjusted for confounding variables. Results Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR], 1.5; 95% confidence interval [CI]: 1.1–1.9) and noncardia gastric cancer (OR, 1.9; 95% CI: 1.3–2.8). The association was strongest for the diffuse histologic type (OR, 3.2; 95% CI: 1.2–10.7). An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR, 0.5; 95% CI: 0.3–0.9), esophageal adenocarcinoma (OR, 0.5; 95% CI: 0.3–0.9), and esophageal squamous cell carcinoma (OR, 0.4; 95% CI: 0.2–0.9). Conclusions The rs2294008 polymorphism in PSCA increases the risk of noncardia gastric cancer and its precursors in white individuals but protects against proximal cancers.

Published
2011

31. A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3

Author

Ramachandran S. Vasan, Heyo K. Kroemer, Henri Wallaschofski, Nele Friedrich, Florian Ernst, Mark O. Goodarzi, Jenny Manolopoulou, Henry Völzke, Lisa S. Sullivan, Martina Müller, Carolyn S.P. Lam, Ariadni Spyroglou, Norman Klopp, Christian Gieger, Jerome I. Rotter, Howard D. Strickler, Matthias Nauck, H.-Erich Wichmann, Martin Bidlingmaier, Robert C. Kaplan, Reiner Biffar, Anne B. Newman, Qiong Yang, Ming-Huei Chen, Kenneth Rice, Alexander Teumer, Anne R. Cappola, Angela Döring, Georg Homuth, Michael Pollak, Ann-Kristin Petersen, Nicole L. Glazer, Holly Smith, Douglas B. Sawyer, Y.-D. Ida Chen, Martin Reincke, and Bruce M. Psaty

Subjects
Male, IGFBP3, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, Cohort Studies, Genetics, Humans, Insulin-Like Growth Factor I, Molecular Biology, Gene, Genetics (clinical), Aged, Carbohydrate homeostasis, Cell growth, Association Studies Articles, Chromosome, General Medicine, Insulin-Like Growth Factor Binding Protein 3, Growth-factor-I, Factor-binding protein-3, Breast-cancer risk, Genetic-variation, Factor (IGF)-I, Mortality, Disease, Polymorphism, Deficiency, Hormone, Female, Chromosomes, Human, Pair 7, Genome-Wide Association Study
Abstract

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

Published
2011

32. Common variation in the ADAM8 gene affects serum sADAM8 concentrations and the risk of myocardial infarction in two independent cohorts

Author

Ari-Pekka J. Huovila, Mari Levula, Norman Klopp, Pekka Kuukasjärvi, Terho Lehtimäki, Reijo Laaksonen, Mika Kähönen, Niku Oksala, Ilkka Seppälä, Emma Raitoharju, Pekka J. Karhunen, Markku Pelto-Huikko, Jari Viik, Thomas Illig, Jari Laurikka, Kjell Nikus, Rami Lehtinen, and Matti Tarkka

Subjects
Male, Risk, Heterozygote, medicine.medical_specialty, Pathology, Genotype, Myocardial Infarction, Enzyme-Linked Immunosorbent Assay, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, SNP, RNA, Messenger, Myocardial infarction, Allele, Gene, Alleles, Finland, Aged, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, Genetic Variation, Membrane Proteins, Middle Aged, Prognosis, medicine.disease, 3. Good health, ADAM Proteins, Phenotype, Gene Expression Regulation, Angiography, Female, ADAM8 Gene, Cardiology and Cardiovascular Medicine, ADAM8
Abstract

The single nucleotide polymorphism (SNP) rs2995300 in the metalloproteinase-disintegrin gene ADAM8 has been shown to affect the areas of complicated coronary plaques and the risk of fatal myocardial infarction (MI) in men. This study was set up to further investigate the role of ADAM8 in MI.To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk.Samples from the Finnish cardiovascular study (FINCAVAS, N=2156) and the angiography and genes study (ANGES, N=1000) were genotyped. Serum sADAM8 concentrations were determined with ELISA (N=443). ADAM8 mRNA levels in atherosclerotic plaques were analysed from the tampere vascular study (TVS, N=53) samples.A significantly increased MI risk for carriers of the rs2995300C allele and the rs2275725 A allele was revealed in the meta-analysis of the ANGES and FINCAVAS patient data (OR=1.42, P0.001 and OR=1.43, P0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations.The risk alleles of the investigated ADAM8 SNPs were associated with elevated sADAM8 serum levels and MI risk. The present results implicate ADAM8 in the development of CVDs and suggest its prognostic and therapeutic potential.

Published
2011
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33. A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

Author

Juergen Schrezenmeir, Heidi Rossmann, Joshua C. Bis, Tanja Zeller, Heinz Erich Wichmann, Sandra Wilde, Jeanette Erdmann, Serkalem Demissie, Wibke Reinhard, Roberto Elosua, Arne Schillert, Vilmundur Gudnason, Albert Hofman, Sekar Kathiresan, Philipp S. Wild, Christoph Bickel, François Cambien, Stefan Schreiber, Mary Susan Burnett, Eric Boerwinkle, Klaus Stark, Nour Eddine El Mokthari, Stefan Blankenberg, Mingyao Li, Veikko Salomaa, Medea S. Eleftheriadis, Marcus E. Kleber, Dominique Arveiler, Alun Evans, Kaisa Silander, Jarmo Virtamo, Michael M. Hoffmann, Arne Schäfer, Andreas Ziegler, Patrick Diemert, Till Keller, Aaron R. Folsom, Peter S. Braund, Annette Peters, Karl J. Lackner, Nehal N. Mehta, Stephen M. Schwartz, Nilesh J. Samani, Inke R. König, Heribert Schunkert, Renate B. Schnabel, Jens Baumert, L. Adrienne Cupples, André G. Uitterlinden, Tamara B. Harris, Muredach P. Reilly, Per-Gunnar Wiklund, Hans J. Rupprecht, Maja Barbalić, Jaqueline C M Witteman, Frank Kee, Jean Ferrières, Edith Lubos, Hendrik B. Sager, David S. Siscovick, Liming Qu, Norman Klopp, Daniel J. Rader, Thomas Münzel, Joseph M. Devaney, Hakon Hakonarson, Benjamin F. Voight, Stephen E. Epstein, Emmanuelle Yon, Albert V. Smith, Silke Szymczak, Claire Perret, Christoph Sinning, Diana Rubin, Maryam Kavousi, David Altshuler, Laurence Tiret, Carole Proust, Christopher J. O'Donnell, John R. Thompson, Winfried März, Olli Saarela, Arne Deiseroth, Thomas Illig, Philippe Amouyel, Christian Hengstenberg, Olle Melander, Kari Kuulasmaa, Alistair S. Hall, Epidemiology, and Internal Medicine

Subjects
Genomics, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, Monocytes, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Genetics, coronary artery disease, genome-wide association studies, gene expression, genetic variation, genomics, eQTL, eSNP, LIPA, Humans, Genetic Predisposition to Disease, Genetics(clinical), RNA, Messenger, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Chromosomes, Human, Pair 10, Gene Expression Profiling, Genetic Variation, Sterol Esterase, medicine.disease, Gene expression profiling, Case-Control Studies, Expression quantitative trait loci, Endothelium, Vascular, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background— eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results— In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P −3 . Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene ( P =3.7×10 −8 ; odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript ( P =1.3×10 −96 ). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function ( P =4.4×10 −3 ). Conclusions— The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA , located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

Published
2011
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34. miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study

Author

Mari Levula, Matti Tarkka, Niku Oksala, Terho Lehtimäki, Pekka J. Karhunen, Mika Kähönen, Ari Mennander, Thomas Illig, Norman Klopp, Leo-Pekka Lyytikäinen, Emma Raitoharju, and Reijo Laaksonen

Subjects
Male, Pathology, medicine.medical_specialty, Population, Down-Regulation, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, microRNA, medicine, Humans, Mammary Arteries, education, Aged, 030304 developmental biology, 0303 health sciences, education.field_of_study, Messenger RNA, Gene Expression Profiling, MicroRNA Expression Profile, Middle Aged, Plaque, Atherosclerotic, Up-Regulation, Gene expression profiling, MicroRNAs, medicine.anatomical_structure, Female, Cardiology and Cardiovascular Medicine, Mirna microarray, Artery
Abstract

MicroRNAs are small non-coding RNAs that inversely regulate their target gene expression. The whole miRNA profile of human atherosclerotic plaques has not been studied previously. The aim of this study was to investigate the miRNA expression profile in human atherosclerotic plaques as compared to non-atherosclerotic left internal thoracic arteries (LITA), and to connect this expression to the processes in atherosclerosis.The miRNA expression profiles of six LITAs and 12 atherosclerotic plaques obtained from aortic, carotid, and femoral atherosclerotic arteries from Tampere Vascular Study were analyzed. The analyses were performed with Agilent's miRNA Microarray. The expression levels of over 4-fold up-regulated miRNAs were verified with qRT-PCR from a larger population (n=50). Messenger RNA levels were analyzed with Illumina's Expression BeadChip to study miRNA target expression.Ten miRNAs were found to be differently expressed in atherosclerotic plaques when compared to controls (p0.05). The expression of miR-21, -34a, -146a, -146b-5p, and -210 was verified and found to be significantly up-regulated in atherosclerotic arteries versus LITAs (p0.001, fold changes 4.61, 2.55, 2.87, 2.82, and 3.92, respectively). Several predicted targets of these miRNAs were down-regulated, and gene set enrichment analysis showed several pathways which could be differently expressed due to this miRNA profile.The microRNA expression profile differs significantly between atherosclerotic plaques and control arteries. The most up-regulated miRNAs are involved in processes known to be connected to atherosclerosis. Interfering with the miRNA expression in the artery wall is a potential way to affect atherosclerotic plaque and cardiovascular disease development.

Published
2011
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35. Common Variants at Abca7, Ms4A6A/Ms4A4E, Epha1, Cd33 and Cd2Ap Are Associated with Alzheimer'S Disease

Author

Neill R. Graff-Radford, Caroline S. Widdowson, John Hardy, Simon Lovestone, Stefan Schreiber, Ana Frank-García, Amy Gerrish, Kevin Mayo, Alexandra Stretton, Michael John Owen, Minerva M. Carrasquillo, Seth Love, Jade Chapman, Vincent Chouraki, Monique M.B. Breteler, Francesco Panza, Emma R L C Vardy, Ronald C. Petersen, Harald Hampel, S. Nicolhaus, Lenore J. Launer, Michelle K. Lupton, Eckart Rüther, A. David Smith, David C. Rubinsztein, Rebecca Sims, Gill Livingston, Diana Zelenika, Simon Mead, Martin N. Rossor, Hilkka Soininen, Christine Van Broeckhoven, Kristel Sleegers, Thorlakur Jonsson, M. Arfan Ikram, Helen Beaumont, Michael Conlon O'Donovan, Federico Licastro, Sudha Seshadri, Alexander Richards, Nick C. Fox, Markus M. Nöthen, Claudine Berr, T. Feulner, Benedetta Nacmias, Carlos Cruchaga, Peter Passmore, Oscar L. Lopez, Julie Williams, Matthias Riemenschneider, Florence Pasquier, John Gallacher, Didier Hannequin, Sigrid Botne Sando, Jens Wiltfang, Charlene Thomas, Gabriele Siciliano, Maria Barcikowska, Mikko Hiltunen, Carol Brayne, Dobril Ivanov, Anita L. DeStefano, Bernadette McGuinness, Norman Klopp, Gordon K. Wilcock, Aoibhinn Lynch, Wolfgang Maier, Peter Holmans, H.-Erich Wichmann, Giorgio Annoni, Beatrice Arosio, Alison Goate, Sigurbjorn Bjornsson, Karl-Heinz Jöckel, Dan Rujescu, Hugh Gurling, Nigel M. Hooper, Clive Holmes, Andrew McQuillin, Patricia Friedrich, John Powell, Rhian Gwilliam, R. Heun, Jacques Epelbaum, Isabella Heuser, Magda Tsolaki, Dennis W. Dickson, Alberto Pilotto, Stephen Todd, Dominique Campion, Michael Krawczak, Jan O. Aasly, Olivier Hanon, Patrick G. Kehoe, Johannes Kornhuber, Marc Delepine, Peter Paul De Deyn, Britta Schürmann, Brian A. Lawlor, Christophe Tzourio, Richard Abraham, Petra Nowotny, Jean-François Dartigues, Heike Kölsch, Michelangelo Mancuso, Marian L. Hamshere, Zbigniew K. Wszolek, Paola Piccardi, Paolo Bosco, Jean-Charles Lambert, Denise Harold, Frank Jessen, Palmi V. Jonsson, Paola Bossù, Paul Hollingworth, Jon Snaedal, Michael Gill, Onofre Combarros, David M. A. Mann, John C. Morris, Annette L. Fitzpatrick, Christopher Shaw, Alexis Brice, Philippe Amouyel, Elio Scarpini, Lesley Jones, Sebastiaan Engelborghs, Daniela Galimberti, Vincenzo Solfrizzi, V. Shane Pankratz, John Collinge, María J. Bullido, Kristelle Brown, Nicholas Bass, Andrew B. Singleton, Jaspreet Singh Pahwa, Kari Stefansson, Lutz Frölich, Steven G. Younkin, Ignacio Mateo, Annick Alpérovitch, Benjamin Genier-Boley, Ina Giegling, Caterina Riehle, Kimberley Dowzell, Mark Lathrop, Hreinn Stefansson, Sandro Sorbi, Rita Guerreiro, Thomas W. Mühleisen, Karolien Bettens, Michael Hüll, Martin Dichgans, Petroula Proitsi, Panagiotis Deloukas, Valentina Moskvina, Cornelia M. van Duijn, Donald Warden, Victoria Alvarez, Eliecer Coto, Kevin Morgan, Susanne Moebus, Ammar Al-Chalabi, Elisa Porcellini, Stefan Wagenpfeil, Hendrik van den Bussche, John S. K. Kauwe, Stacy Steinberg, David Craig, Nicola Jones, Manuel Mayhaus, Davide Seripa, Neurology, NCA - Neurodegeneration, HOLLINGWORTH P, HAROLD D, SIMS R, GERRISH A, LAMBERT JC, CARRASQUILLO MM, ABRAHAM R, HAMSHERE ML, PAHWA JS, MOSKVINA V, DOWZELL K, JONES N, STRETTON A, THOMAS C, RICHARDS A, IVANOV D, WIDDOWSON C, CHAPMAN J, LOVESTONE S, POWELL J, PROITSI P, LUPTON MK, BRAYNE C, RUBINSZTEIN DC, GILL M, LAWLOR B, LYNCH A, BROWN KS, PASSMORE PA, CRAIG D, MCGUINNESS B, TODD S, HOLMES C, MANN D, SMITH AD, BEAUMONT H, WARDEN D, WILCOCK G, LOVE S, KEHOE PG, HOOPER NM, VARDY ER, HARDY J, MEAD S, FOX NC, ROSSOR M, COLLINGE J, MAIER W, JESSEN F, RÜTHER E, SCHÜRMANN B, HEUN R, KÖLSCH H, VAN DEN BUSSCHE H, HEUSER I, KORNHUBER J, WILTFANG J, DICHGANS M, FRÖLICH L, HAMPEL H, GALLACHER J, HÜLL M, RUJESCU D, GIEGLING I, GOATE AM, KAUWE JS, CRUCHAGA C, NOWOTNY P, MORRIS JC, MAYO K, SLEEGERS K, BETTENS K, ENGELBORGHS S, DE DEYN PP, VAN BROECKHOVEN C, LIVINGSTON G, BASS NJ, GURLING H, MCQUILLIN A, GWILLIAM R, DELOUKAS P, AL-CHALABI A, SHAW CE, TSOLAKI M, SINGLETON AB, GUERREIRO R, MÜHLEISEN TW, NÖTHEN MM, MOEBUS S, JÖCKEL KH, KLOPP N, WICHMANN HE, PANKRATZ VS, SANDO SB, AASLY JO, BARCIKOWSKA M, WSZOLEK ZK, DICKSON DW, GRAFF-RADFORD NR, PETERSEN RC, ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE, VAN DUIJN CM, BRETELER MM, IKRAM MA, DESTEFANO AL, FITZPATRICK AL, LOPEZ O, LAUNER LJ, SESHADRI S, CHARGE CONSORTIUM, BERR C, CAMPION D, EPELBAUM J, DARTIGUES JF, TZOURIO C, ALPÉROVITCH A, LATHROP M, EADI1 CONSORTIUM, FEULNER TM, FRIEDRICH P, RIEHLE C, KRAWCZAK M, SCHREIBER S, MAYHAUS M, NICOLHAUS S, WAGENPFEIL S, STEINBERG S, STEFANSSON H, STEFANSSON K, SNAEDAL J, BJÖRNSSON S, JONSSON PV, CHOURAKI V, GENIER-BOLEY B, HILTUNEN M, SOININEN H, COMBARROS O, ZELENIKA D, DELEPINE M, BULLIDO MJ, PASQUIER F, MATEO I, FRANK-GARCIA A, PORCELLINI E, HANON O, COTO E, ALVAREZ V, BOSCO P, SICILIANO G, MANCUSO M, PANZA F, SOLFRIZZI V, NACMIAS B, SORBI S, BOSSÙ P, PICCARDI P, AROSIO B, ANNONI G, SERIPA D, PILOTTO A, SCARPINI E, GALIMBERTI D, BRICE A, HANNEQUIN D, LICASTRO F, JONES L, HOLMANS PA, JONSSON T, RIEMENSCHNEIDER M, MORGAN K, YOUNKIN SG, OWEN MJ, O'DONOVAN M, AMOUYEL P, WILLIAMS J, Epidemiology, Radiology & Nuclear Medicine, Clinical sciences, Pathologic Biochemistry and Physiology, Hollingworth, P, Harold, D, Sims, R, Gerrish, A, Lambert, J, Carrasquillo, M, Abraham, R, Hamshere, M, Pahwa, J, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Thomas, C, Richards, A, Ivanov, D, Widdowson, C, Chapman, J, Lovestone, S, Powell, J, Proitsi, P, Lupton, M, Brayne, C, Rubinsztein, D, Gill, M, Lawlor, B, Lynch, A, Brown, K, Passmore, P, Craig, D, Mcguinness, B, Todd, S, Holmes, C, Mann, D, Smith, A, Beaumont, H, Warden, D, Wilcock, G, Love, S, Kehoe, P, Hooper, N, Vardy, E, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Rüther, E, Schürmann, B, Heun, R, Kölsch, H, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Gallacher, J, Hüll, M, Rujescu, D, Giegling, I, Goate, A, Kauwe, J, Cruchaga, C, Nowotny, P, Morris, J, Mayo, K, Sleegers, K, Bettens, K, Engelborghs, S, De Deyn, P, Van Broeckhoven, C, Livingston, G, Bass, N, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Al Chalabi, A, Shaw, C, Tsolaki, M, Singleton, A, Guerreiro, R, Mühleisen, T, Nöthen, M, Moebus, S, Jöckel, K, Klopp, N, Wichmann, H, Pankratz, V, Sando, S, Aasly, J, Barcikowska, M, Wszolek, Z, Dickson, D, Graff Radford, N, Petersen, R, van Duijn, C, Breteler, M, Ikram, M, Destefano, A, Fitzpatrick, A, Lopez, O, Launer, L, Seshadri, S, Berr, C, Campion, D, Epelbaum, J, Dartigues, J, Tzourio, C, Alpérovitch, A, Lathrop, M, Feulner, T, Friedrich, P, Riehle, C, Krawczak, M, Schreiber, S, Mayhaus, M, Nicolhaus, S, Wagenpfeil, S, Steinberg, S, Stefansson, H, Stefansson, K, Snædal, J, Björnsson, S, Jonsson, P, Chouraki, V, Genier Boley, B, Hiltunen, M, Soininen, H, Combarros, O, Zelenika, D, Delepine, M, Bullido, M, Pasquier, F, Mateo, I, Frank Garcia, A, Porcellini, E, Hanon, O, Coto, E, Alvarez, V, Bosco, P, Siciliano, G, Mancuso, M, Panza, F, Solfrizzi, V, Nacmias, B, Sorbi, S, Bossù, P, Piccardi, P, Arosio, B, Annoni, G, Seripa, D, Pilotto, A, Scarpini, E, Galimberti, D, Brice, A, Hannequin, D, Licastro, F, Jones, L, Holmans, P, Jonsson, T, Riemenschneider, M, Morgan, K, Younkin, S, Owen, M, O'Donovan, M, Amouyel, P, and Williams, J

Subjects
Male, ABCA7 protein, human, ATP-Binding Cassette Transporters/genetics, Sialic Acid Binding Ig-like Lectin 3, CD33, SORL1, Medizin, genetics [Alzheimer Disease], Adaptor Proteins, Signal Transducing/genetics, Disease, PICALM, ABCA7, Disease susceptibility, 0302 clinical medicine, genetics [Adaptor Proteins, Signal Transducing], Databases, Genetic, GWAS, GENE-EXPRESSION, Medicine(all), Aged, 80 and over, Genetics, 0303 health sciences, Alzheimer's disease, genetic predisposition, Receptor, EphA1, ALZHEIMER’S DISEASE, Antigens, CD/genetics, genetics [Receptor, EphA1], genetics [Membrane Proteins], Multigene Family, Female, genetics [Antigens, Differentiation, Myelomonocytic], APOE, Antigens, Differentiation, Myelomonocytic, Single-nucleotide polymorphism, Case-control studies, Cytoskeletal Proteins/genetics, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, CD33 protein, human, Alzheimer Disease, Antigens, CD, ddc:570, Humans, Genetic Predisposition to Disease, Membrane Proteins/genetics, CLUSTERIN, Aged, genetics [Cytoskeletal Proteins], Adaptor Proteins, Signal Transducing, 030304 developmental biology, Alzheimer Disease/genetics, Antigens, Differentiation, Myelomonocytic/genetics, Genetic Variation, Membrane Proteins, CD2-associated protein, genetics [Antigens, CD], Cytoskeletal Proteins, MS4A4E protein, human, Case-Control Studies, Susceptibility locus, biology.protein, ATP-Binding Cassette Transporters, Human medicine, genetics [ATP-Binding Cassette Transporters], aged, 80 and over, Receptor, EphA1/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ĝ‰Currency sign 1 × 10 -5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 -17; including ADGC data, meta P = 5.0 × 10 -21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 -14; including ADGC data, meta P = 1.2 × 10 -16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 -4; including ADGC data, meta P = 8.6 × 10 -9), CD33 (GERAD+, P = 2.2 × 10 -4; including ADGC data, meta P = 1.6 × 10 -9) and EPHA1 (GERAD+, P = 3.4 × 10 -4; including ADGC data, meta P = 6.0 × 10 -10). © 2011 Nature America, Inc. All rights reserved.

Published
2011

36. Genetic variants harbored in the forkhead box protein 3 locus increase hay fever risk

Author

Thomas Illig, Norman Klopp, Michael Kabesch, Tim Sparwasser, Martin Wetzke, Kathrin Suttner, Erika von Mutius, and Martin Depner

Subjects
Genetics, Genotype, Immunology, Genetic Variation, Rhinitis, Allergic, Seasonal, Forkhead Transcription Factors, Locus (genetics), Single-nucleotide polymorphism, Biology, Linkage Disequilibrium, Gene Frequency, Risk Factors, Germany, Genetic variation, Humans, Immunology and Allergy, Allele, Child, Allele frequency, Gene
Published
2010

37. Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators

Author

Russell P. Tracy, Cathy Tilley, Annette Peters, Norman Klopp, Maja Barbalić, Jens Baumert, Gerardo Heiss, Jennifer F. Yamamoto, Abbas Dehghan, Nancy S. Jenny, Joshua C. Bis, Christian Herder, Jacqueline C.M. Witteman, Martin G. Larson, Stefan Blankenberg, Yanyan Zhu, Alanna C. Morrison, Jeremy D. Walston, Thomas Illig, Ramachandran S. Vasan, Peter Durda, John F. Keaney, Christie M. Ballantyne, Natalie Khuseyinova, Josée Dupuis, Patrick T. Ellinor, Ron C. Hoogeveen, Emelia J. Benjamin, Eric Boerwinkle, Wolfgang Koenig, Renate B. Schnabel, Bruce M. Psaty, Margaret F. Doyle, Christian Gieger, Epidemiology, and Dermatology

Subjects
Adult, Male, CCR2, Chemokine, Erythrocytes, Immunology, Receptors, Cell Surface, Polymorphism, Single Nucleotide, Biochemistry, Proinflammatory cytokine, Cohort Studies, medicine, Humans, Cytokine binding, Receptor, Interleukin 6, Chemokine CCL2, biology, Monocyte, Cell Biology, Hematology, Middle Aged, Molecular biology, medicine.anatomical_structure, Chromosomes, Human, Pair 1, Genetic Loci, biology.protein, Female, Interleukin 18, Inflammation Mediators, Duffy Blood-Group System, Genome-Wide Association Study
Abstract

To identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.0 * 10−323). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene (genome-wide P = 8.0 * 10−13). Asp42Gly accounted for approximately 20% of the variability in serum MCP-1 concentrations and also was associated with serum concentrations of interleukin-8 and RANTES. While exploring a lack of association between this polymorphism and EDTA plasma MCP-1 concentrations (P = .82), we determined that both clotting and exogenous heparan sulfate (unfractionated heparin) released substantial amounts of MCP-1 from Darc. Quantitative immunoflow cytometry failed to identify meaningful Asp42Gly-associated differences in Darc expression, suggesting that a functional change is responsible for the differential cytokine binding. We conclude that Asp42Gly is a major regulator of erythrocyte Darc-mediated cytokine binding and thereby the circulating concentrations of several proinflammatory cytokines. We have also identified for the first time 2 mechanisms for the release of reservoir chemokines with possible clinical implications.

Published
2010

38. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Author

Bruno H. Stricker, Igor Rudan, Kenneth Rice, Karol Estrada, John M. C. Connell, Thomas Meitinger, Ying A. Wang, Mark Eijgelsheim, Stephan B. Felix, Gerjan Navis, Ozren Polasek, Jingyuan Fu, Fernando Rivadeneira, Joshua C. Bis, Elsayed Z. Soliman, James F. Wilson, Albert V. Smith, Alan F. Wright, Heyo K. Kroemer, Albert Hofman, David S. Siscovick, Steven Giovannone, Caroline Hayward, Fangyu Liu, Alvaro Alonso, Rinse K. Weersma, Aaron R. Folsom, Mark J. Caulfield, Alexander Teumer, Glenn I. Fishman, Christopher J. O'Donnell, Kristin D. Marciante, Martina Müller, Tamara B. Harris, Harold Snieder, Arne Pfeufer, Man Li, Andrew A. Hicks, Moritz F. Sinner, Wiek H. van Gilst, Sarah H. Wild, Nona Sotoodehnia, Jared W. Magnani, Leonard H. van den Berg, Patricia B. Munroe, L. Adrienne Cupples, Paul I.W. de Bakker, Jiaxiang Qu, Roel A. Ophoff, Daniel Levy, Mark P.S. Sie, Toby Johnson, Cornelia M. van Duijn, Lude Franke, Jacqueline C.M. Witteman, Tim D. Spector, Claudia B. Volpato, Folkert W. Asselbergs, Aravinda Chakravarti, Rudolf S N Fehrmann, Xiaowen Lu, Astrid Petersmann, Anna F. Dominiczak, Yalda Jamshidi, W. H. Linda Kao, Anna Köttgen, Susan R. Heckbert, Vilmundur Gudnason, H-Erich Wichmann, Nilesh J. Samani, Marcus Dörr, Christopher Newton-Cheh, Jan A. Kors, Thor Aspelund, Harry J.M. Groen, Irene Mateo Leach, Eric Boerwinkle, Gé van Herpen, Ben A. Oostra, Peter P. Pramstaller, Sandosh Padmanabhan, André G. Uitterlinden, Cisca Wijmenga, Dan E. Arking, Dirk J. van Veldhuisen, Rudolf A. de Boer, Bruce M. Psaty, Christine Schwienbacher, Ilja M. Nolte, Thomas J. Wang, Stefan Kääb, Christian Fuchsberger, Norman Klopp, Lenore J. Launer, Henry Völzke, Siegfried Perz, Aaron Isaacs, Sina A. Gharib, Uwe Völker, Harry Campbell, Jerome I. Rotter, Gerard J. te Meerman, Pim van der Harst, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Intensive Care, Internal Medicine, Medical Informatics, and Clinical Genetics

Subjects
Candidate gene, 030204 cardiovascular system & hematology, ELECTROCARDIOGRAM, DISEASE, Sodium Channels, genome-wide, QRS, Electrocardiography, Mice, 0302 clinical medicine, PR INTERVAL, Chromosomes, Human, Myocytes, Cardiac, TRANSCRIPTION FACTOR, GENE-EXPRESSION, Genetics, 0303 health sciences, RICH REPEAT PROTEIN, medicine.diagnostic_test, Models, Animal, Cardiology, cardiovascular system, Electrical conduction system of the heart, medicine.medical_specialty, QT INTERVAL DURATION, HEART-RATE, Mice, Transgenic, Biology, Sudden death, QT interval, Polymorphism, Single Nucleotide, NAV1.8 Voltage-Gated Sodium Channel, 03 medical and health sciences, QRS complex, Heart Conduction System, Internal medicine, medicine, Animals, Humans, cardiovascular diseases, PR interval, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Computational Biology, medicine.disease, Animals, Newborn, Genetic Loci, Heart failure, SYSTEM, Genome-Wide Association Study
Abstract

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Published
2010
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39. Colorectal cancer and polymorphisms in DNA repair genes WRN , RMI1 and BLM

Author

Bernd Frank, Hermann Brenner, Thomas Illig, Jenny Chang-Claude, Michael Hoffmeister, and Norman Klopp

Subjects
Adult, Male, Risk, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, Werner Syndrome Helicase, DNA Repair, Genotype, Colorectal cancer, DNA repair, RecQ helicase, Adenocarcinoma, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, RMI1, Germany, medicine, Humans, Genetic Predisposition to Disease, Allele, Gene, Genotyping, Aged, Aged, 80 and over, Genetics, RecQ Helicases, Nuclear Proteins, nutritional and metabolic diseases, DNA, Neoplasm, General Medicine, Odds ratio, Middle Aged, medicine.disease, DNA-Binding Proteins, Exodeoxyribonucleases, Amino Acid Substitution, Haplotypes, Case-Control Studies, Female, Carrier Proteins, Colorectal Neoplasms
Abstract

RecQ helicase family members are involved in multiple DNA repair pathways, protecting the genome from incorrect recombination during mitosis and maintaining its stability. Deficiencies in genes encoding the RecQ helicases WRN and BLM lead to rare autosomal recessive diseases, Werner and Bloom syndromes, which have been implicated in early onset of aging, and predisposition to various types of cancer. We investigated associations of WRN, BLM and BLM-associated protein (BLAP75/RMI1) gene polymorphisms and risk of colorectal cancer (CRC), genotyping WRN V114I (rs2230009), WRN L1074F (rs2725362), WRN C1367R (rs1346044), RMI1 S455N (rs1982151) and BLM P868L (rs11852361). A large population-based case―control study, including 1795 CRC cases and 1805 controls, found no evidence for an association between the selected allelic variants in DNA repair-related genes and CRC risk. However, we detected a significant association of BLM P868L with an increased rectal cancer risk (odds ratio = 1.29, 95 % confidence interval 1.02―1.64 and P = 0.04), suggesting a potential cancer-site specificity. This is the first study to analyze the associations between polymorphisms in WRN, BLM and RMI1 and CRC risk. Although none of them showed a significant association with CRC, the association of BLM P868L with rectal cancer risk requires further investigation.

Published
2009

40. Functional Characterization of Promoter Variants of the Adiponectin Gene Complemented by Epidemiological Data

Author

Claudia Lamina, Barbara Thorand, Akuma D. Saningong, H.-Erich Wichmann, Jochen Hess, Hans Hauner, Jens Baumert, Iris M. Heid, Wolfgang Rathmann, Norman Klopp, Helmut Laumen, Thomas Illig, Eva-Maria Sedlmeier, Melina Claussnitzer, and Christian Herder

Subjects
Adult, Male, Endocrinology, Diabetes and Metabolism, Population, Single-nucleotide polymorphism, Biology, Transfection, Polymorphism, Single Nucleotide, Cell Line, Mice, Genetics, Adipocytes, Internal Medicine, Animals, Humans, SNP, Cloning, Molecular, Promoter Regions, Genetic, education, Gene, Aged, DNA Primers, education.field_of_study, Adiponectin, Haplotype, Chromosome Mapping, Genetic Variation, Promoter, 3T3 Cells, Middle Aged, Molecular biology, Minor allele frequency, Original Article, Female, Algorithms
Abstract

OBJECTIVE Adiponectin (APM1, ACDC) is an adipocyte-derived protein with downregulated expression in obesity and insulin-resistant states. Several potentially regulatory single nucleotide polymorphisms (SNPs) within the APM1 gene promoter region have been associated with circulating adiponectin levels. None of them have been functionally characterized in adiponectin-expressing cells. Hence, we investigated three SNPs (rs16861194, rs17300539, and rs266729) for their influence on adiponectin promoter activity and their association with circulating adiponectin levels. RESEARCH DESIGN AND METHODS Basal and rosiglitazone-induced promoter activity of different SNP combinations (haplotypes) was analyzed in 3T3-L1 adipocytes using luciferase reporter gene assays and DNA binding studies comparing all possible APM1 haplotypes. This functional approach was complemented with analysis of epidemiological population-based data of 1,692 participants of the MONICA/KORA S123 cohort and 696 participants from the KORA S4 cohort for SNP and haplotype association with circulating adiponectin levels. RESULTS Major to minor allele replacements of the three SNPs revealed significant effects on promoter activity in luciferase assays. Particularly, a minor variant in rs16861194 resulted in reduced basal and rosiglitazone-induced promoter activity and hypoadiponectinemia in the epidemiological datasets. The haplotype with the minor allele in all three SNPs showed a complete loss of promoter activity, and no subject carried this haplotype in either of the epidemiological samples (combined P value for statistically significant difference from a random sample was 0.006). CONCLUSIONS Our results clearly demonstrate that promoter variants associated with hypoadiponectinemia in humans substantially affect adiponectin promoter activity in adipocytes. Our combination of functional experiments with epidemiological data overcomes the drawback of each approach alone.

Published
2008

41. Quantifying the contribution of genetic variants for survival phenotypes

Author

Helmut Küchenhoff, Martina Müller, Norman Klopp, Caren Vollmert, Angela Döring, Heike Bickeböller, H.-Erich Wichmann, Florian Kronenberg, Claudia Lamina, Joachim Heinrich, Dörthe Malzahn, Iris M. Heid, and Christa Meisinger

Subjects
Epidemiology, Population, Single-nucleotide polymorphism, Deviance (statistics), Biology, Polymorphism, Single Nucleotide, 01 natural sciences, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Statistics, Econometrics, Humans, Computer Simulation, Genetic Predisposition to Disease, Mortality, 0101 mathematics, education, Genetics (clinical), Survival analysis, Proportional Hazards Models, Genetic association, Likelihood Functions, education.field_of_study, Models, Genetic, Proportional hazards model, Explained variation, Phenotype, 030220 oncology & carcinogenesis, Censoring (clinical trials)
Abstract

Particularly in studies based on population representative samples, it is of major interest what impact a genetic variant has on the phenotype of interest, which cannot be answered by mere association estimates alone. One possible measure for quantifying the phenotype's variance explained by the genetic variant is R2. However, for survival outcomes, no clear definition of R2 is available in the presence of censored observations. We selected three criteria proposed for this purpose in the literature and compared their performance for single nucleotide polymorphism (SNP) data through simulation studies and for mortality data with candidate SNPs in the general population-based KORA cohort. The evaluated criteria were based on: (1) the difference of deviance residuals, (2) the variation of individual survival curves, and (3) the variation of Schoenfeld residuals. Our simulation studies included various censoring and genetic scenarios. The simulation studies revealed that the deviance residuals' criterion had a high dependence on the censoring percentage, was generally not limited to the range [0; 1] and therefore lacked interpretation as a percentage of explained variation. The second criterion (variation of survival curves) hardly reached values above 60%. Our requirements were best fulfilled by the criterion based on Schoenfeld residuals. Our mortality data analysis also supported the findings in simulation studies. With the criterion based on Schoenfeld residuals, we recommend a powerful and flexible tool for genetic epidemiological studies to refine genetic association studies by judging the contribution of genetic variants to survival phenotype. Genet. Epidemiol. 2008. © 2008 Wiley-Liss, Inc.

Published
2008

42. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects

Author

Florian Kronenberg, Norman Klopp, Henry Völzke, Divya Mehta, Christa Meisinger, Stefan Coassin, Kathleen Henke, Holger Prokisch, Guido Fischer, Angela Döring, H-Erich Wichmann, Arne Pfeufer, Christian Gieger, Henning Gohlke, Dieter Rosskopf, Thomas Meitinger, Thomas Illig, and Bernhard Paulweber

Subjects
Adult, Male, medicine.medical_specialty, Genotype, Gout, Glucose Transport Proteins, Facilitative, Polymorphism, Single Nucleotide, Urate transport, chemistry.chemical_compound, Germany, Internal medicine, Diabetes mellitus, Genetics, medicine, Humans, Sex Distribution, Aged, Aged, 80 and over, biology, Genome, Human, Computational Biology, Middle Aged, medicine.disease, Uric Acid, Minor allele frequency, Endocrinology, chemistry, Austria, Case-Control Studies, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Study of Health in Pomerania, biology.protein, Uric acid, Female, SLC22A12, Biomarkers, SLC2A9
Abstract

Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.

Published
2008

43. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author

Laura J. Scott, Neil Robertson, Anders Hamsten, Domenico Palli, Susanne Moebus, Bernhard O. Boehm, Gunnar Sigurðsson, Paul W. Franks, C. N. A. Palmer, Sonali Pechlivanis, Katharine R. Owen, Michael E. Reschen, Sarah Edkins, Jason Carey, Christopher A. O’Callaghan, Norman Klopp, Caroline S. Fox, Petter Storm, N. William Rayner, Johan G. Eriksson, Thomas Illig, Anubha Mahajan, Erik Ingelsson, Allan Linneberg, Andrew R. Wood, Oddgeir L. Holmen, Nicola L. Beer, Mark I. McCarthy, Frank B. Hu, Peter Almgren, Heiner Boeing, Peter Donnelly, Carl Platou, Veikko Salomaa, Karl-Heinz Jöcke, Wen-Hong L. Kao, Lori L. Bonnycastle, Denis Rybin, Benjamin F. Voight, Peter Kraft, Inês Barroso, Claudia Langenberg, Teresa Ferreira, Peter Kovacs, Anne Raimondo, Christian Theil Have, Ulf de Faire, Torben Hansen, Han Chen, James B. Meigs, Timothy M. Frayling, Noël P. Burtt, Gerald Steinbach, Eric Boerwinkle, Michael Stumvoll, Stefan Gustafsson, Lars Lind, Andrew D. Morris, Alena Stančáková, Panagiotis Deloukas, Kari Stefansson, Augustine Kong, Hans A. Kestler, Andrew T. Hattersley, Beverley Balkau, Lorenzo Pasquali, Yingchang Lu, Nicola D. Kerrison, George B. Grant, Eeva Korpi-Hyövälti, Steven Wiltshire, Karl Gertow, Jorge Ferrer, Barbara Thorand, Inga Prokopenko, Matthias Blüher, Yvonne T. van der Schouw, Olga McLeod, Oluf Pedersen, Leena Peltonen, Anil Chalisey, Eleftheria Zeggini, Joseph Trakalo, Eric J.G. Sijbrands, Rainer Rauramaa, Guillaume Charpentier, Satu Männistö, Cordelia Langford, Lewin Eisele, Damiano Baldassarre, Lennart C. Karssen, Rona J. Strawbridge, Ghazala Mirza, Peter S. Chines, Roman Wennauer, Sara M. Willems, Erwin P. Bottinger, Timo Saaristo, Stéphane Cauchi, Ching-Ti Liu, Martijn van de Bunt, Valgerdur Steinthorsdottir, David Altshuler, Hyun Min Kang, Michael Boehnke, Jaakko Tuomilehto, Peter M. Nilsson, Kyle J. Gaulton, Jian'an Luan, Loic Yengo, David Couper, Reedik Mägi, Harald Grallert, Simone Wahl, Juha Saltevo, Phoenix Kwan, Cecilia M. Lindgren, Peter Lichtner, Richard N. Bergman, Andrew Crenshaw, João Fadista, Michael Roden, Annette Peters, Robert A. Scott, Unnur Thorsteinsdottir, James S. Pankow, Yeji Lee, Cornelia M. van Duijn, Samuli Ripatti, Francis S. Collins, Stéphane Lobbens, Niels Grarup, Ruth J. F. Loos, Julia Meyer, Marit E. Jørgensen, Christian Herder, Inger Njølstad, John R. B. Perry, Markus M. Nöthen, Man Li, Martina Müller-Nurasyid, Valeriya Lyssenko, Pierre Fontanillas, Michael D. Linderman, Leena Kinnunen, Jana K. Rundle, Elena Tremoli, Marilyn C. Cornelis, Tanya M. Teslovich, Todd Green, Raimund Erbel, Elisabeth M. van Leeuwen, Bengt Sennblad, Olle Melander, Sirkka Keinänen-Kiukaanniemi, Markku Laakso, Eero Lindholm, Alex S. F. Doney, Anke Tönjes, Maija Hassinen, Thomas W. Mühleisen, Gonçalo R. Abecasis, Nancy L. Pedersen, Thomas Sparsø, Johanna Kuusisto, Dorothée Thuillier, Qi Sun, Ian Dunham, Himanshu Chheda, Adam E. Locke, Philippe Froguel, Nicholas J. Wareham, Bruna Gigante, Jose C. Florez, Mozhgan Dorkhan, Omri Gottesman, Liming Liang, Anna Jonsson, Tiinamaija Tuomi, Leif Groop, Steve E. Humphries, Heikki A. Koistinen, Kristian Hveem, Astradur B. Hreidarsson, Jason Flannick, Torben Jørgensen, Clement Ma, Mattias Frånberg, Ewan Birney, Andrew P. Morris, Timo A. Lakka, Rob M. van Dam, Heather M. Stringham, Christian Gieger, Elodie Eury, Konstantin Strauch, Anna L. Gloyn, Rafn Benediktsson, Andres Metspalu, David J. Hunter, Karen L. Mohlke, Gudmar Thorleifsson, Josée Dupuis, Emmi Tikkanen, Christian Fuchsberger, Evelin Mihailov, Christopher J. Groves, Soren K. Thomsen, Tõnu Esko, Anne U. Jackson, Karin Leander, Douglas M. Ruderfer, Nikolay Oskolkov, Sekar Kathiresan, Robert Sladek, Lu Qi, Jasmina Kravic, Carmen Navarro, Epidemiology, Dermatology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Stanford Univ, Dept Genet, Stanford, CA 94305 USA [ 3 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 4 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England [ 5 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 6 ] Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England [ 7 ] Wellcome Trust Sanger Inst, Hinxton, England [ 8 ] Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England [ 9 ] Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England [ 10 ] Broad Inst Harvard & MIT, Cambridge, MA USA [ 11 ] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark [ 12 ] European Genom Inst Diabet, Lille Inst Biol, Lille, France [ 13 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 14 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany [ 15 ] German Ctr Diabet Res, Neuherberg, Germany [ 16 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 17 ] Sci Life Lab, Stockholm, Sweden [ 18 ] Stockholm Univ, Dept Numer Anal & Comp Sci, S-10691 Stockholm, Sweden [ 19 ] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany [ 20 ] Univ Ulm, Med Syst Biol, D-89069 Ulm, Germany [ 21 ] Finnish Inst Mol Med, Helsinki, Finland [ 22 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 23 ] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 24 ] deCODE Genet Amgen Inc, Reykjavik, Iceland [ 25 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 26 ] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA [ 27 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA [ 28 ] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA [ 29 ] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA [ 30 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 31 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 32 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 33 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 34 ] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA [ 35 ] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA [ 36 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 37 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 38 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 39 ] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy [ 40 ] Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France [ 41 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 42 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 43 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 44 ] Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany [ 45 ] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany [ 46 ] German Inst Human Nutr, Potsdam, Germany [ 47 ] NHGRI, US NIH, Bethesda, MD 20892 USA [ 48 ] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA [ 49 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 50 ] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA [ 51 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 52 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 53 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Ctr Diabet Res, Dundee, Scotland [ 54 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 55 ] Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Novo Nordisk Scandinavia, Malmo, Sweden [ 56 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 57 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 58 ] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland [ 59 ] Folkhalsan Res Ctr, Helsinki, Finland [ 60 ] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA [ 61 ] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA [ 62 ] CNRS, UMR 8199, Inst Biol, Lille, France [ 63 ] Univ Lille 2, Inst Pasteur, Lille, France [ 64 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 65 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 66 ] Harvard Univ, Sch Med, Boston, MA USA [ 67 ] Lund Univ, Dept Clin Sci, Malmo, Sweden [ 68 ] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden [ 69 ] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 70 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 71 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 72 ] Partner Site Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany [ 73 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway [ 74 ] UCL, Inst Cardiovasc Sci, British Heart Fdn BHF Labs, Cardiovasc Genet, London, England [ 75 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 76 ] Steno Diabet Ctr, DK-2820 Gentofte, Denmark [ 77 ] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark [ 78 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 79 ] Aalborg Univ, Fac Med, Aalborg, Denmark [ 80 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 81 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany [ 82 ] Rigshosp, Copenhagen Univ Hosp, DK-2100 Copenhagen, Denmark [ 83 ] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark [ 84 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany [ 85 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Guys & St Thomas Hosp, Genom Core Facil, Biomed Res Ctr, London, England [ 86 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 87 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 88 ] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany [ 89 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 90 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany [ 91 ] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany [ 92 ] Inst Murciano Invest Biosanitaria Virgen de la Ar, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain [ 93 ] CIBERESP, Madrid, Spain [ 94 ] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain [ 95 ] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England [ 96 ] Canc Res & Prevent Inst ISPO, Florence, Italy [ 97 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 98 ] Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 99 ] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA [ 100 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 101 ] Univ Med Ctr Utrecht, Utrecht, Netherlands [ 102 ] Iceland Heart Assoc, Kopavogur, Iceland [ 103 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 104 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 105 ] Univ Ulm, Dept Clin Chem & Cent Lab, D-89069 Ulm, Germany [ 106 ] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland [ 107 ] Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland [ 108 ] Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland [ 109 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 110 ] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England [ 111 ] European Mol Biol Lab, EBI, Hinxton, England [ 112 ] Germans Trias & Pujol Univ Hosp & Res Inst, Div Endocrinol, Badalona, Spain [ 113 ] Josep Carreras Leukaemia Res Inst, Badalona, Spain [ 114 ] CIBERDEM, Barcelona, Spain [ 115 ] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England [ 116 ] Inst Invest Biomed August Pi & Sunyer, Ctr Esther Koplowitz, Barcelona, Spain [ 117 ] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA [ 118 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 119 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 120 ] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA [ 121 ] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA [ 122 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 123 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 124 ] Netherlands Consortium Hlth Ageing, Netherlands Genom Initiat, Rotterdam, Netherlands [ 125 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 126 ] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA [ 127 ] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland [ 128 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 129 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 130 ] Univ Uppsala Hosp, Dept Med Sci, Uppsala, Sweden [ 131 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 132 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 133 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 134 ] Finnish Diabet Assoc, Tampere, Finland [ 135 ] Pirkanmaa Dist Hosp, Tampere, Finland [ 136 ] Cent Finland Cent Hosp, Dept Med, Jyvasklya, Finland [ 137 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 138 ] Univ Duisdurg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 139 ] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland [ 140 ] Univ Med Ctr Ulm, Dept Internal Med, Div Endocrinol & Diabet, Ulm, Germany [ 141 ] Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, London SW7 2AZ, England [ 142 ] Nanyang Technol Univ, Singapore 639798, Singapore [ 143 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 144 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 145 ] Univ Helsinki, Cent Hosp, Dept Med, Div Endocrinol, Helsinki, Finland [ 146 ] Minerva Fdn, Helsinki, Finland [ 147 ] Hosp Univ La Paz, Inst Invest Sanitaria, Madrid, Spain [ 148 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 149 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 150 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 151 ] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England [ 152 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 153 ] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England [ 154 ] Ctr Hosp Univ Montreal, Ctr Rech, Montreal Diabet Res Ctr, Montreal, PQ, Canada [ 155 ] McGill Univ, Montreal, PQ, Canada [ 156 ] Genome Quebec Innovat Ctr, Montreal, PQ, Canada [ 157 ] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark [ 158 ] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland [ 159 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 160 ] Univ Cambridge, Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Cambridge, England [ 161 ] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 162 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 163 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 164 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England [ 165 ] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
endocrine system diseases, Medizin, Genome-wide association study, Glucose homeostasis, WIDE ASSOCIATION, Association mapping, Non-U.S. Gov't, Genome-Wide Association Study, Regulation of gene expression, Genetics, Genetics & Heredity, LARGE-SCALE ASSOCIATION, Research Support, Non-U.S. Gov't, COMMON VARIANTS, Chromosome Mapping, 11 Medical And Health Sciences, Genomics, 3. Good health, TRANSCRIPTION FACTORS, Liver, Hepatocyte Nuclear Factor 3-beta, Medical Genetics, Life Sciences & Biomedicine, Chromatin Immunoprecipitation, endocrine system, European Continental Ancestry Group/genetics, Biology, GENOTYPE IMPUTATION, Research Support, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, N.I.H, Sykursýki, Islets of Langerhans, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, HUMAN PANCREATIC-ISLETS, GLYCEMIC TRAITS, Journal Article, SNP, Humans, Genetic Predisposition to Disease, Comparative Study, Enhancer, Medicinsk genetik, Science & Technology, Binding Sites, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Receptor, Melatonin, MT2, Extramural, Molecular Sequence Annotation, Arfgengi, 06 Biological Sciences, Genetic Predisposition to Disease/genetics, BETA-CELL, Diabetes Mellitus, Type 2/genetics, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Loci, Case-Control Studies, Gene-Environment Interaction, GLUCOSE-HOMEOSTASIS, Chromatin immunoprecipitation, Developmental Biology
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. cademy of Finland 77299 102318 10493 118065 123885 124243 129293 129680 136895 139635 211119 213506 251217 263836 Agence National de la Recherche Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques Association Diabeete Risque Vasculaire Association Francaise des Diabetiques Association of Danish Pharmacies Augustinus Foundation Becket Foundation British Diabetes Association (BDA) Research British Heart Foundation Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) City of Kuopio City of Leutkirch Copenhagen County Danish Centre for Evaluation and Health Technology Assessment Danish Council for Independent Research Danish Heart Foundation Danish Research Councils Deutsche Forschungsgemeinschaft ER 155/6-2 Diabetes Research Foundation Diabetes UK Doris Duke Charitable Foundation Erasmus Medical Center Erasmus University Estonian government SF0180142s08 European Commission ENGAGE HEALTH-F4-2007-201413 FP7-201413 FP7-245536 EXGENESIS LSHM-CT-2004-005272 FP6 LSHM_CT_2006_037197 LSHM-CT-2007-037273 C-Public Health 2004310 European Regional Development Fund Federal Ministry of Education and Research, Germany FKZ 01GI1128 FKZ 01EO1001 Federal Ministry of Health, Germany Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Society Folkhalsan Research Foundation Foundation for Life and Health in Finland Foundation for Old Servants Fredrick och Ingrid Thuring Foundation French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Region) German Center for Diabetes Research German Research Council GRK1041 German National Genome Research Network Groupe d'Etude des Maladies Metaboliques et Systemiques Health Care Centers in Vasa, Narpes and Korsholm, Finland Health Foundation Heinz Nixdorf Foundation Helmholtz Zentrum Munchen Helsinki University Central Hospital Research Foundation Hospital District of Southwest Finland Ib Henriksens Foundation IngaBritt and Arne Lundberg's Research Foundation 359 Karolinska Institutet Knut and Alice Wallenberg Foundation KAW 2009.0243 Kuopio University Hospital Lundbeck Foundation Magnus Bergvall Foundation Medical Faculty of University Duisburg-Essen Medical Research Council, UK G0000649 G0601261 Ministry for Health, Welfare and Sports, the Netherlands Ministry of Education and Culture, Finland 722 627 Ministry of Education, Culture and Science, the Netherlands Ministry of Health and Prevention, Denmark Ministry of Social Affairs and Health, Finland Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany Munich Center of Health Sciences Municipal Health Care Center and Hospital in Jakobstad, Finland municipality of Rotterdam, the Netherlands Narpes Health Care Foundation National Health Screening Service of Norway National Heart, Lung, and Blood Institute, USA HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C N01HC25195 N02HL64278 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute, USA U01HG004402 N01HG65403 National Institute for Diabetes and Digestive and Kidney Diseases, USA R01DK078616 U01DK085526 K24DK080140 R01DK073490 National Institute for Health and Welfare, Finland National Institutes of Health, USA HHSN268200625226C UL1RR025005 R01DK062370 R01DK072193 1Z01HG000024 AG028555 AG08724 AG04563 AG10175 AG08861 U01HG004399 DK58845 CA055075 DK085545 DK098032 Netherlands Genomics Initiative Netherlands Organisation for Health Research and Development Netherlands Organisation of Scientific Research NOW Investments 175.010.2005.011 911-03-012 050-060-810 Nord-Trondelag County Council Nordic Center of Excellence in Disease Genetics Norwegian Institute of Public Health Norwegian Research Council Novo Nordisk Foundation Ollquist Foundation Oxford National Institute for Health Research (NIHR) Biomedical Research Centre Paavo Nurmi Foundation Paivikki and Sakari Sohlberg Foundation Perklen Foundation Pirkanmaa Hospital District, Finland Programme Hospitalier de Recherche Clinique Programme National de Recherche sur la Diabete Research Institute for Diseases in the Elderly 014-93-015 Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center Royal Swedish Academy of Sciences Sarstedt, Germany Signe and Ane Gyllenberg Foundation Sigrid Juselius Foundation Slottery Machine Association, Finland Social Insurance Institution of Finland South OstroBothnia Hospital District state of Baden-Wurttemberg, Germany Stockholm County Council 560183 Swedish Cultural Foundation, Finland Swedish Diabetes Foundation Swedish e-science Research Center Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation Swedish Research Council SFO EXODIAB 2009-1039 521-2010-3490 521-2007-4037 521-2008-2974 ANDIS 825-2010-5983 LUDC 349-2008-6589 8691 Swedish Society of Medicine Tore Nilsson Foundation Torsten and Ragnar Soderbergs Stiftelser MT33/09 University Hospital Essen University of Tromso University College London NIHR Biomedical Research Centre UK NIHR Cambridge Biomedical Research Centre Uppsala University Uppsala University Hospital Vaasa Hospital District Velux Foundation Wellcome Trust GR072960 076113 083948 090367 090532 083270 086596 098017 095101 098051 098381

Published
2015

44. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations

Author

Elke Rodriguez, Claudia Jenneck, Markus M. Nöthen, Colin N. A. Palmer, Natalija Novak, Laura Maintz, Johannes Ring, Stefan Wagenpfeil, Tobias Hagemann, Stephan Weidinger, W.H. Irwin McLean, Heidrun Behrendt, Norman Klopp, Yiwei Zhao, Simon P. Lee, Hansjörg Baurecht, Thomas Illig, Haihui Liao, Alan D. Irvine, and Amalia Diaz-Lacava

Subjects
Allergy, integumentary system, Immunology, Atopic dermatitis, Filaggrin Proteins, Immunoglobulin E, Biology, medicine.disease, Dermatitis, Atopic, Allergic sensitization, Atopy, Intermediate Filament Proteins, Genetic linkage, Case-Control Studies, Mutation, Genotype, atopic dermatitis, skin barrier, epidermal differentiation complex, filaggrin, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Skin, Filaggrin, Ichthyosis vulgaris
Abstract

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. OBJECTIVES: Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. METHODS: We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. RESULTS: Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. CONCLUSION: Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. CLINICAL IMPLICATIONS: These findings underline the crucial role of the skin barrier in preventing allergic sensitization. &nbsp

Published
2006

45. A genome-wide expression quantitative trait loci analysis of proprotein convertase subtilisin/kexin enzymes identifies a novel regulatory gene variant for FURIN expression and blood pressure

Author

Leo-Pekka Lyytikäinen, Mari Levula, Hannu Turpeinen, Ilkka Seppälä, Emma Raitoharju, Terho Lehtimäki, Norman Klopp, Marko Pesu, Reijo Laaksonen, Niku Oksala, Nina Hutri-Kähönen, Thomas Illig, Melanie Waldenberger, Olli T. Raitakari, Mika Kähönen, and Nina Mononen

Subjects
Male, Quantitative Trait Loci, Genome-wide association study, Single-nucleotide polymorphism, Blood Pressure, Biology, Polymorphism, Single Nucleotide, Gene Expression Regulation, Enzymologic, Genetics, Humans, Subtilisins, Furin, Gene, Genetics (clinical), Regulation of gene expression, Serine Endopeptidases, Proprotein convertase, Molecular biology, Expression quantitative trait loci, biology.protein, Kexin, Female, Vascular Resistance, Proprotein Convertases, Genome-Wide Association Study
Abstract

Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized. To gain a comprehensive understanding of the genetic regulation of PCSK expression, we performed, for the first time, a genome-wide expression quantitative trait loci (eQTL) analysis using mRNA expression in >1400 human peripheral blood samples from the Cardiovascular Risk in Young Finns Study and ca. ten million single-nucleotide polymorphisms (SNPs). The expression data showed clear expression for FURIN, PCSK5, PCSK7 and MBTPS1 (membrane-bound transcription factor peptidase, site 1) mRNAs in virtually all tested samples. A discovery analysis demonstrated a genome-wide significant (p

Published
2014

46. Polymorphisms in extracellular signal-regulated kinase family influence genetic susceptibility to asthma

Author

Norman Klopp, Maximilian Schieck, Andrea von Berg, Andre Franke, Aristea Binia, Thomas Frischer, Michael Kabesch, Albrecht Bufe, Jon Genuneit, Ramesh Chandra Pandey, Burkhard Simma, Sven Michel, Thomas Illig, Otto Laub, Andrea Heinzmann, Ernst Rietschel, and Liming Liang

Subjects
Genetics, business.industry, Extracellular signal-regulated kinases, Immunology, Intracellular Signaling Peptides and Proteins, Case-control study, Protein Serine-Threonine Kinases, Biology, medicine.disease, Polymorphism, Single Nucleotide, Asthma, Cell Line, Text mining, Cell culture, Case-Control Studies, medicine, Genetic predisposition, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Extracellular Signal-Regulated MAP Kinases, business
Abstract

Asthma susceptibility loci determined by genome-wide association studies explain only a fraction of asthma's hereditability. Pathway analysis has emerged as a next step toward mining hidden genetic factors in complex diseases. Arecent study investigating the association between polymorphisms in Toll-like receptor signaling pathways and asthma revealed that 2 members of the mitogen-activated protein kinase (MAPK) pathway (MAP kinase kinase 3 and extracellular signal-regulated kinase 2 [ERK2]) showed strong association with the disease

Published
2013

47. Ethylnitrosourea-Induced Base Pair Substitution Affects Splicing of the Mouse γE-Crystallin Encoding Gene Leading to the Expression of a Hybrid Protein and to a Cataract

Author

Jana Löster, Jack Favor, Jochen Graw, Norman Klopp, and Angelika Neuhäuser-Klaus

Subjects
Alkylating Agents, RNA Splicing, Recombinant Fusion Proteins, Molecular Sequence Data, Biology, medicine.disease_cause, Cataract, Frameshift mutation, Mice, Crystallin, Complementary DNA, Genetics, medicine, Animals, gamma-Crystallins, Gene, Mutation, Base Sequence, Point mutation, Intron, Chromosome Mapping, Crystallins, Molecular biology, eye diseases, Mutagenesis, Ethylnitrosourea, RNA splicing, sense organs, Research Article
Abstract

A novel ENU-induced mutation in the mouse leading to a nuclear and cortical opacity of the eye lens (ENU418) was mapped to proximal chromosome 1 by a genome-wide mapping approach. It suggests that the cluster of γ-crystallin encoding genes (Cryg) and the βA2-crystallin encoding gene Cryba2 are excellent candidate genes. An A → G exchange in the middle of intron 1 of the Cryge gene was found as the only alteration cosegregating with the cataractous phenotype. The mutation was confirmed by the presence of a novel restriction site for ApaI in the corresponding genomic DNA fragment. The mutation represses splicing of intron 1; the additional 92 bp in the corresponding cDNA leads to a frameshift and the expression of a novel hybrid protein containing 3 amino acids of the γE-crystallin at the N terminus, but 153 novel amino acids. The CrygeENU418 protein has a calculated molecular mass of ∼15.6 kD and an alkaline isoelectric point (pH 10.1) and is predicted to have two hydrophobic domains. Western blot analysis using a polyclonal antibody against the hydrophilic C-terminal part of the CrygeENU418-specific protein demonstrated its stable expression in the cataractous lenses; it was not found in the wild types. Histological analysis of the cataractous lenses indicated that the expression of the new protein disrupts the cellular structure of the eye lens.

Published
2002

48. Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels

Author

Andrea von Berg, Michaela Schedel, Aristea Binia, Burkard Simma, Norman Klopp, Michael Kabesch, Vincent D. Gaertner, Albrecht Bufe, Otto Laub, Sven Michel, Martin Depner, Jon Genuneit, Thomas Illig, Maximilian Schieck, Ernst Rietschel, Andrea Heinzmann, Antoaneta A. Toncheva, Marie T. Rieger, and Christian Vogelberg

Subjects
Male, Linkage disequilibrium, Genotype, International Cooperation, Immunology, Population, DNA Mutational Analysis, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Th2 Cells, Germany, Gene expression, Transcriptional regulation, Immunology and Allergy, Humans, Genetic Predisposition to Disease, education, Child, Promoter Regions, Genetic, Th1-Th2 Balance, Cells, Cultured, Asthma, Ormdl3, T(h)2 Cytokine, Association Study, Chromosome 17q21, Polymorphism, Promoter Activity, Transcriptional Regulation, Upstream Stimulatory Factor, education.field_of_study, Interleukin-13, Haplotype, Membrane Proteins, Cross-Sectional Studies, Gene Expression Regulation, Haplotypes, Case-Control Studies, Leukocytes, Mononuclear, Female, Interleukin-4, Chromosomes, Human, Pair 17
Abstract

BACKGROUND: Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies. OBJECTIVE: We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility. METHODS: We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n=3557 total subjects, n=281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n=1446 total subjects, n=763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele-specific effects on transcription factor binding and promoter activity invitro and gene expression in PBMCs after stimulation ex vivo. RESULTS: Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P=9.9×10(-5) and P=.0035, respectively) and case-control (P=3.15×10(-8) and P=.0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed invitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels exvivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression. CONCLUSION: Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in TH2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.

Published
2014

49. Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms

Author

Melina Claussnitzer, Simon N. Dankel, Bernward Klocke, Harald Grallert, Viktoria Glunk, Tea Berulava, Heekyoung Lee, Nikolay Oskolkov, Joao Fadista, Kerstin Ehlers, Simone Wahl, Christoph Hoffmann, Kun Qian, Tina Rönn, Helene Riess, Martina Müller-Nurasyid, Nancy Bretschneider, Timm Schroeder, Thomas Skurk, Bernhard Horsthemke, Derek Spieler, Martin Klingenspor, Martin Seifert, Michael J. Kern, Niklas Mejhert, Ingrid Dahlman, Ola Hansson, Stefanie M. Hauck, Matthias Blüher, Peter Arner, Leif Groop, Thomas Illig, Karsten Suhre, Yi-Hsiang Hsu, Gunnar Mellgren, Hans Hauner, Helmut Laumen, Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. Hofmann, Josée Dupuis, Lu Qi, Ayellet V. Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S.F. Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U. Jackson, Paul R.V. Johnson, Torben Jørgensen, Wen H.L. Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Narisu Narisu, Peter Nilsson, Katharine R. Owen, Felicity Payne, John R.B. Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N. William Rayner, Neil R. Robertson, Ghislain Rocheleau, Michael Roden, Michael J. Sampson, Richa Saxena, Beverley M. Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M. Stringham, Qi Sun, Amy J. Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M. van Dam, Timon W. van Haeften, Thijs van Herpt, Jana V. van Vliet-Ostaptchouk, G. Bragi Walters, Michael N. Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N. Bergman, Stephane Cauchi, Francis S. Collins, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, Karen L. Mohlke, Andrew D. Morris, Colin N.A. Palmer, Peter P. Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J. Wareham, Richard M. Watanabe, Goncalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, H.-Erich Wichmann, Inês Barroso, Jose C. Florez, Timothy M. Frayling, Rob Sladek, Unnur Thorsteinsdottir, James F. Wilson, Philippe Froguel, Cornelia M. van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I. McCarthy, Clinical sciences, Johnson, P, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
Diabetes risk, SUSCEPTIBILITY LOCI, Medizin, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Endocrinology and Diabetes, Biology, PHOSPHOENOLPYRUVATE CARBOXYKINASE, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, 0302 clinical medicine, insulin resistance, Animals, Humans, EPIGENOMIC ANALYSIS, GENOME-WIDE ASSOCIATION, genome, Gene, Transcription factor, IN-VIVO, Cells, Cultured, Conserved Sequence, 030304 developmental biology, Genetic association, Homeodomain Proteins, Regulation of gene expression, Genetics, 0303 health sciences, Biochemistry, Genetics and Molecular Biology(all), INSULIN SENSITIVITY, Research Support, Non-U.S. Gov't, LARGE-SCALE, GENE, PPAR gamma, DNA binding site, ADIPOSE-TISSUE, Diabetes Mellitus, Type 2, Gene Expression Regulation, transcription factor binding sites, Homeobox, PPAR-GAMMA, type 2 diabetes, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors
Abstract

SummaryGenome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.

Published
2014

50. A common atopy-associated variant in the TH2 cytokine locus control region impacts transcriptional regulation and alters SMAD3 and SP1 binding

Author

Stefanie M. Hauck, C. von Toerne, Karl-Werner Schramm, Norman Klopp, Hansjörg Baurecht, Melina Claussnitzer, Helmut Laumen, Kilian Eyerich, Andre Franke, Jerzy Adamski, Holger Prokisch, Simone Wahl, Annette Peters, Stephan Weidinger, Heekyoung Lee, M. Waldenberger, Alexander Teumer, Thomas Illig, Eva Reischl, Stefanie Eyerich, Lili Milani, Axel Kretschmer, and Gabriele Möller

Subjects
Hypersensitivity, Immediate, Transcription, Genetic, Sp1 Transcription Factor, Immunology, Repressor, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Regulatory Sequences, Nucleic Acid, Jurkat cells, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Th2 Cells, Gene Order, Transcriptional regulation, Immunology and Allergy, Humans, Position-Specific Scoring Matrices, Smad3 Protein, Nucleotide Motifs, Promoter Regions, Genetic, Transcription factor, Locus control region, Alleles, Rad50, Rhs7, Atopic Diseases, Functional Snp, Rs2240032, Genetics, Binding Sites, Locus Control Region, Gene Expression Regulation, Cytokines, Protein Binding
Abstract

Background Type 2 immune responses directed by Th2 cells and characterized by the signature cytokines IL4, IL5, and IL13 play major pathogenic roles in atopic diseases. Single nucleotide polymorphisms in the human Th2 cytokine locus in particular in a locus control region within the DNA repair gene RAD50, containing several RAD50 DNase1-hypersensitive sites (RHS), have been robustly associated with atopic traits in genome-wide association studies (GWAS). Functional variants in IL13 have been intensely studied, whereas no causative variants for the IL13-independent RAD50 signal have been identified yet. This study aimed to characterize the functional impact of the atopy-associated polymorphism rs2240032 located in the human RHS7 on cis-regulatory activity and differential binding of transcription factors. Methods Differential transcription factor binding was analyzed by electrophoretic mobility shift assays (EMSAs) with Jurkat T-cell nuclear extracts. Identification of differentially binding factors was performed using mass spectrometry (LC-MS/MS). Reporter vector constructs carrying either the major or minor allele of rs2240032 were tested for regulating transcriptional activity in Jurkat and HeLa cells. Results The variant rs2240032 impacts transcriptional activity and allele-specific binding of SMAD3, SP1, and additional putative protein complex partners. We further demonstrate that rs2240032 is located in an RHS7 subunit which itself encompasses repressor activity and might be important for the fine-tuning of transcription regulation within this region. Conclusion The human RHS7 critically contributes to the regulation of gene transcription, and the common atopy-associated polymorphism rs2240032 impacts transcriptional activity and transcription factor binding.

Published
2014

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